N-aryl(thio)anthranilic acid amide derivatives, their preparation and their use as VEGF receptor tyrosine kinase inhibitors

ABSTRACT

Described are compounds of formula (I), wherein W is O or S; X is NR 8 ; Y is CR 9 R 10 -(CH 2 )n wherein R 9  and R 10  are independently of each other hydrogen or lower alkyl, and n is an integer of from and including 0 to and including 3; or Y is SO 2 ; R 1  is aryl; R 2  is a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms with the exception that R 2  cannot represent 2-phthalimidyl, and in case of Y═SO 2  cannot represent 2,1,3-benzothiadiazol-4-yl; any of R 3 , R 4 , R 5  and R 6 , independently of the other, is H or a substituent other than hydrogen; and R 7  and R 8 , independently of each other, are H or lower alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical product for the treatment of a neoplastic disease which responds to an inhibition of the VEGF receptor tyrosine kinase activity. The compounds of formula (I) can be used for the treatment e.g. of a neoplastic disease, such as a tumor disease, of retinopathy and age-related macular degeneration.

[0001] The invention relates to new benzamide derivatives, processes forthe preparation thereof, the application thereof in a process for thetreatment of the human or animal body, the use thereof—alone or incombination with one or more other pharmaceutically active compounds—forthe treatment especially of a neoplastic disease, such as a tumordisease, of retinopathy and age-related macular degeneration; a methodfor the treatment of such a disease in animals, especially in humans,and the use of such a compound—alone or in combination with one or moreother pharmaceutically active compounds—for manufacture of apharmaceutical preparation (medicament) for the treatment of aneoplastic disease, of retinopathy and age-related macular degeneration.

[0002] Certain diseases are known to be associated with deregulatedangiogenesis, for example diseases caused by ocular neovascularisation,such as retinopathies (including diabetic retinopathy), age-relatedmacula degeneration, psoriasis, haemangioblastoma, haemangioma,arteriosclerosis, an inflammatory disease, such as a rheumatoid orrheumatic inflammatory disease, especially arthritis, such as rheumatoidarthritis, or other chronic inflammatory disorders, such as chronicasthma, arterial or post-transplantational atherosclerosis,endometriosis, and especially neoplastic diseases, for example so-calledsolid tumours and liquid tumours (such as leucemias).

[0003] According to recent findings, at the centre of the networkregulating the growth and differentiation of the vascular system and itscomponents, both during embryonic development and normal growth and in awide number of pathological anomalies and diseases, lies the angiogenicfactor known as “Vascular Endothelial Growth Factor” (=VGEF; originallytermed “Vascular Permeability Factor”, =VPF), along with its cellularreceptors (see Breier, G., et al., Trends in Cell Biology 6, 454-6[1996] and references cited therein).

[0004] VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein and isrelated to “Platelet-Derived Growth Factor” (PDGF). It is produced bynormal cell lines and tumor cell lines, is an endothelial cell-specificmitogen, shows angiogenic activity in in vivo test systems (e.g. rabbitcornea), is chemotactic for endothelial cells and monocytes, and inducesplasminogen activators in endothelial cells, which are then involved inthe proteolytic degradation of extracellular matrix during the formationof capillaries. A number of isoforms of VEGF are known, which showcomparable biological activity, but differ in the type of cells thatsecrete them and in their heparin-binding capacity. In addition, thereare other members of the VEGF family, such as “Placenta Growth Factor”(PLGF) and VEGF-C.

[0005] VEGF receptors are transmembranous receptor tyrosine kinases.They are characterized by an extracellular domain with sevenimmunoglobulin-like domains and an intracellular tyrosine kinase domain.Various types of VEGF receptor are known, e.g. VEGFR-1, VEGFR-2, andVEGFR-3.

[0006] A large number of human tumors, especially gliomas andcarcinomas, express high levels of VEGF and its receptors. This has ledto the hypothesis that the VEGF released by tumor cells could stimulatethe growth of blood capillaries and the proliferation of tumorendothelium in a paracrine manner and thus, through the improved bloodsupply, accelerate tumor growth. Increased VEGF expression could explainthe occurrence of cerebral oedema in patients with glioma. Directevidence of the role of VEGF as a tumor angiogenesis factor in vivo hasbeen obtained from studies in which VEGF expression or VEGF activity wasinhibited. This was achieved with antibodies which inhibit VEGFactivity, with dominant-negative VEGFR-2 mutants which inhibited signaltransduction, or with the use of antisense-VEGF RNA techniques. Allapproaches led to a reduction in the growth of glioma cell lines orother tumor cell lines in vivo as a result of inhibited tumorangiogenesis.

[0007] Angiogenesis is regarded as an absolute prerequisite for thosetumors which grow beyond a maximum diameter of about 1-2 mm; up to thislimit, oxygen and nutrients may be supplied to the tumor cells bydiffusion. Every tumor, regardless of its origin and its cause, is thusdependent on angiogenesis for its growth after it has reached a certainsize.

[0008] Three principal mechanisms play an important part in the activityof angiogenesis inhibitors against tumors: 1) Inhibition of the growthof vessels, especially capillaries, into avascular resting tumors, withthe result that there is no net tumor growth owing to the balance thatis achieved between apoptosis and proliferation; 2) Prevention of themigration of tumor cells owing to the absence of blood flow to and fromtumors; and 3) Inhibition of endothelial cell proliferation, thusavoiding the paracrine growth-stimulating effect exerted on thesurrounding tissue by the endothelial cells which normally line thevessels.

[0009] Surprisingly, it has now been found that benzamide derivatives offormula I, described below, are a new class of compounds that haveadvantageous pharmacological properties and inhibit, for example, theactivity of the VEGF receptor tyrosine kinase, the growth of tumors andVEGF-dependent cell proliferation, or the treatment of especiallyinflammatory rheumatic or rheumatoid diseases, such as rheumatoidarthritis, and/or pain, or the other diseases mentioned above and below.

[0010] The compounds of formula I open up, for example, an unexpectednew therapeutic approach, especially for diseases in the treatment ofwhich, and also for the prevention of which, an inhibition ofangiogenesis and/or of the VEGF receptor tyrosine kinase showsbeneficial effects.

FULL DESCRIPTION OF THE INVENTION

[0011] The invention relates the use of a compound of formula I,

[0012] wherein

[0013] W is O or S;

[0014] X is NR₈;

[0015] Y is CR₉R₁₀-(CH₂)_(n) wherein

[0016] R₉ and R₁₀ are independently of each other hydrogen or loweralkyl, and

[0017] n is an integer of from and including 0 to and including 3; or

[0018] Y is SO₂;

[0019] R₁ is aryl;

[0020] R₂ is a mono- or bicyclic heteroaryl group comprising one or morering nitrogen atoms with the exception that R₂ cannot represent2-phthalimidyl, and in case of Y═SO₂ cannot represent2,1,3-benzothiadiazol-4-yl;

[0021] any of R₃, R₄, R₅ and R₆, independently of the other, is H or asubstituent other than hydrogen; and

[0022] R₇ and R₈, independently of each other, are H or lower alkyl;

[0023] or a N-oxide or a pharmaceutically acceptable salt thereof forthe preparation of a pharmaceutical product for the treatment of aneoplastic disease which responds to an inhibition of the VEGF receptortyrosine kinase activity.

[0024] The general terms used hereinbefore and hereinafter preferablyhave within the context of this disclosure the following meanings,unless otherwise indicated:

[0025] The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either linear or branched withsingle or multiple branching.

[0026] Where the plural form is used for compounds, salts, and the like,this is taken to mean also a single compound, salt, or the like.

[0027] Any asymmetric carbon atoms (for example in compounds of formulaI, wherein R₉ is lower alkyl) may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration. Thecompounds may thus be present as mixtures of isomers or as pure isomers,preferably as enantiomer-pure diastereomers.

[0028] The invention relates also to possible tautomers of the compoundsof formula I.

[0029] Lower alkyl is preferably alkyl with from and including 1 up toand including 7, preferably from and including 1 to and including 4, andis linear or branched; preferably, lower alkyl is butyl, such asn-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl orisopropyl, ethyl or preferably methyl.

[0030] The index n is preferably 0 or 1, especially 0.

[0031] Y is preferably methylene (CH₂) or ethylene (CH₂—CH₂), mostpreferably methylene.

[0032] “Aryl” is an aromatic radical which is bound to the molecule viaa bond located at an aromatic ring carbon atom of the radical. In apreferred embodiment, aryl is an aromatic radical having 6 to 14 carbonatoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl orphenanthrenyl, and is unsubstituted or substituted by one or more,preferably up to three, especially one or two substituents, especiallyselected from amino, mono- or disubstituted amino, halogen, alkyl,substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro,cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl,N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, ureido,mercapto, sulfo, lower alkylthio, phenyl, phenoxy, phenylthio,phenyl-lower alkylthio, alkylphenylthio, lower alkylsulfinyl,phenylsulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, loweralkanesulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl,alkylphenylsulfonyl, lower alkenyl, lower alkanoyl, halogen-loweralkylmercapto, halogen-lower alkylsulfonyl, such as especiallytrifluoromethane sulfonyl, dihydroxybora (-B(OH)₂), heterocyclyl, andlower alkylene dioxy bound at adjacent C-atoms of the ring, such asmethylene dioxy; aryl is preferably phenyl or naphthyl, which in eachcase is either unsubstituted or independently substituted by one or twosubstituents selected from the group comprising halogen, especiallyfluorine, chlorine, or bromine; hydroxy; hydroxy, etherified by loweralkyl, e.g. methyl, or by halogen-lower alkyl, e.g. trifluoromethyl;esterified carboxy, especially lower alkoxy carbonyl, e.g. methoxycarbonyl, n-propoxy carbonyl or iso-propoxy carbonyl; N-mono-substitutedcarbamoyl, in particular carbamoyl monosubstituted by lower alkyl, e.g.methyl, n-propyl or isopropyl; lower alkyl, especially methyl, ethyl orpropyl; substituted alkyl, especially lower alkyl, e.g. methyl or ethyl,substituted by lower alkoxy carbonyl, e.g. methoxy carbonyl or ethoxycarbonyl; halogen-lower alkyl, especially trifluoromethyl; loweralkylsulfinyl, such as methylsulfinyl, and lower alkanesulfonyl, such asmethane sulfonyl. Aryl is preferably 3- or 4-chlorophenyl,3-bromophenyl, 4-phenoxyphenyl, 2, 3- or 4-methylphenyl,4-methoxyphenyl, 3- or 4-tert-butylphenyl, 4-n-propylphenyl,4-trifluoromethylphenyl, 3-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 3,4-(trifluoromethyl)phenyl,3-fluoro-4-methylphenyl, 3-chloro-4-methylphenyl,4-chloro-3-trifluoromethylphenyl, 3-chloro-5-trifluoromethylphenyl,4-methylsulfinylphenyl, 4-methanesulfonylphenyl, 4-biphenyl, naphthyl,2-naphthyl; tetrahydronaphthyl, in particular5,6,7,8-tetrahydronaphthyl; hydroxynaphthyl, in particular7-hydroxynaphthyl, 8-hydroxynaphthyl or 8-hydroxy-2-naphthyl;methoxynaphthyl, in particular 4-methoxy-2-naphthyl; halonaphthyl, inparticular 4-chloronaphthyl or 3-bromo-2-naphthyl.

[0033] Mono- or disubstituted amino is especially amino substituted byone or two radicals selected independently of one another from loweralkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl;phenyl-lower alkyl; lower alkanoyl, such as acetyl; benzoyl; substitutedbenzoyl, wherein the phenyl radical is especially substituted by one ormore, preferably one or two, substituents selected from nitro, amino,halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano,carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; andphenyl-lower alkoxycarbonyl, wherein the phenyl radical is unsubstitutedor especially substituted by one or more, preferably one or two,substituents selected from nitro, amino, halogen, N-lower alkylamino,N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl,lower alkanoyl, and carbamoyl; and is preferably N-lower alkylamino,such as N-methylamino, hydroxy-lower alkylamino, such as2-hydroxyethylamino, phenyl-lower alkylamino, such as benzylamino,N,N-di-lower alkylamino, N-phenyl-lower alkyl-N-lower alkylamino,N,N-di-lower alkylphenylamino, lower alkanoylamino, such as acetylamino,or a substituent selected from the group comprising benzoylamino andphenyl-lower alkoxycarbonylamino, wherein the phenyl radical in eachcase is unsubstituted or especially substituted by nitro or amino, oralso by halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino,hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoylor aminocarbonylamino.

[0034] Halogen is especially fluorine, chlorine, bromine, or iodine,especially fluorine, chlorine, or bromine.

[0035] In the preferred embodiment, alkyl has up to a maximum of 12carbon atoms and is especially lower alkyl, especially methyl, or alsoethyl, n-propyl, isopropyl, or tert-butyl.

[0036] Substituted alkyl is alkyl as last defined, especially loweralkyl, preferably methyl; where one or more, especially up to three,substituents may be present, primarily from the group selected fromhalogen, especially fluorine, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, loweralkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl isespecially preferred.

[0037] Etherified hydroxy is especially C₈-C₂₀alkyloxy, such asn-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy,isopropyloxy, or n-pentyloxy, phenyl-lower alkoxy, such as benzyloxy, oralso phenyloxy, or as an alternative or in addition to the previousgroup C₈-C₂₀alkyloxy, such as n-decyloxy, halogen-lower alkoxy, such astrifluoromethyloxy or 1,1,2,2-tetrafluoroethoxy.

[0038] Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy,lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-loweralkoxycarbonyloxy, such as benzyloxycarbonyloxy.

[0039] Esterified carboxy is especially lower alkoxycarbonyl, such astert-butoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl orethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.

[0040] Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl,e.g. acetyl. N-mono- or N,N-disubstituted carbamoyl is especiallysubstituted by one or two substituents independently selected from loweralkyl, phenyl-lower alkyl, and hydroxy-lower alkyl, at the terminalnitrogen atom.

[0041] Alkylphenylthio is especially lower alkylphenylthio.

[0042] Alkylphenylsulfonyl is especially lower alkylphenylsulfonyl.

[0043] Alkylphenylsulfinyl is especially lower alkylphenylsulfinyl.

[0044] Heterocyclyl is especially a five or six-membered heterocyclicsystem with 1 or 2 heteroatoms selected from the group comprisingnitrogen, oxygen, and sulfur, which may be unsaturated or wholly orpartly saturated, and is unsubstituted or substituted especially bylower alkyl, such as methyl; a radical selected from2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3dioxolan-2-yl,1H-pyrazol-3-yl, and 1-methyl-pyrazol-3-yl is preferred.

[0045] Aryl in the form of phenyl which is substituted by lower alkylenedioxy bound to two adjacent C-atoms, such as methylenedioxy, ispreferably 3,4-methylenedioxyphenyl.

[0046] Heteroaryl refers to a heterocyclic moiety that is unsaturated inthe ring binding the heteroaryl radical to the rest of the molecule informula I and is preferably mono-, bi- or tricyclic, preferably mono- orbicyclic; where at least in the binding ring, but optionally also in anyannealed ring, one or more, preferably 1 to 4, most preferably 3 or 4,carbon atoms are replaced each by a heteroatom selected from the groupconsisting of nitrogen, oxygen and sulfur; where the binding ringpreferably has 5 to 12, more preferably 5 to 7 ring atoms; and may beunsubstituted or substituted by one or more, especially one or two,substitutents selected from the group defined above as substitutents foraryl, most preferably by lower alkyl, such as methyl; preferablyheteroaryl is selected from thienyl, furyl, pyranyl, thianthrenyl,isobenzoiuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl,lower-alkyl substituted imidazolyl, benzimidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl,cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl and furazanyl; more preferably selectedfrom the group consisting of triazolyl, especially 1,2,4-triazolyl,1,2,3-triazolyl or 1,3,4-triazolyl, pyridyl, especially 2-, 3 or4-pyridyl, indolyl, especially 3-indolyl, lower-alkylthiazolyl,especially 2-(4-methylthiazolyl), pyrrolyl, especially 1-pyrrolyl, loweralkylimidazolyl, especially 4-(1-methylimidazolyl),4-(2-methylimidazolyl) or 4-(5-methylimidazolyl), benzimidazolyl, suchas 1-benzimidazolyl, or tetrazolyl, such as 5-(1,2,3,4-tetrazolyl).

[0047] A mono- or bicyclic heteroaryl group comprising one or more ringnitrogen atoms is preferably a heteroaryl group as defined above forheteroaryl, with the proviso that preferably at least one nitrogen ispresent as ring heteroatom in the binding ring (that is, the ring fromwhich the bond starts that binds the heteroaryl moiety to the rest ofthe molecule) and with the exception that R₂ cannot represent2-phthalimidyl, and in case of Y═SO₂ R₂ cannot represent2,1,3-benzothiadiazol-4-yl. Preferred is imidazolyl, especiallyimidazol-4-yl, quinolyl, especially 3-, 4-, 5quinolyl, naphthyridinyl,especially 3-(1,8-naphthyridinyl) or 4-(1,8-naphthyridinyl), orespecially a moiety of the formula Ib or Ic

[0048] wherein

[0049] r is 0 to 2,

[0050] A, B, D, and E are, independently of one another, N or CH, withthe stipulation that not more than 2 of these radicals are N;preferably, each of A, B, D and E is CH; and Q is lower alkyl,especially methyl, hydroxy, lower alkoxy, especially methoxy, lowerthioalkyl, especially methylthio, or halogen, especially fluoro, chloroor bromo.

[0051] Very preferably R₂ is 3-pyridyl, 4-pyridyl, 4-quinolinyl or5-quinolinyl. Most preferably, R₂ is 4-pyridyl.

[0052] A substituent other than hydrogen is preferably selected fromamino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl,hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy,esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstitutedcarbamoyl, amidino, guanidino, mercapto, sulfo, lower alkylthio,phenylthio, phenyl-lower alkylthio, alkylphenylthio, loweralkylsulfinyl, phenylsulfinyl, phenyl-lower alkylsulfinyl,alkylphenylsulfinyl, lower alkanesulfonyl, phenylsulfonyl, phenyl-loweralkylsulfonyl, alkylphenylsulfonyl, lower alkenyl, lower alkanoyl,halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, such asespecially trifluoromethane sulfonyl and heterocyclyl. Two substitutentsother than hydrogen bound at adjacent C-atoms of the ring can alsorepresent lower alkylene dioxy, such as methylene dioxy ethylene dioxy.Preferably, a substituent other than hydrogen is lower alkyl or halogen,especially methyl, chloro or fluoro.

[0053] Preferably, R₇ and N are hydrogen, and R₃, R₄, R₅ and R₆ each areindependently hydrogen, chloro or fluorine.

[0054] Salts are especially the pharmaceutically acceptable salts ofcompounds of formula I.

[0055] Such salts are formed, for example, as acid addition salts,preferably with organic or inorganic acids, from compounds of formula Iwith a basic nitrogen atom, especially the pharmaceutically acceptablesalts. Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,malic acid, tartaric acid, citric acid, amino acids, such as glutamicacid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleicacid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoicacid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylaceticacid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid,2-hydroxyethanesulfonic add, ethane-1,2-disulfonic acid, benzenesulfonicacid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3-or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuricacid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-,N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids,such as ascorbic acid.

[0056] In the presence of negatively charged radicals, such as carboxyor sulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts, or ammonium salts withammonia or suitable organic amines, such as tertiary monoamines, forexample triethylamine or tri(2-hydroxyethyl)amine, or heterocyclicbases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.

[0057] When a basic group and an acid group are present in the samemolecule, a compound of formula 1 may also form internal salts.

[0058] For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

[0059] In view of the close relationship between the novel compounds infree form and those in the form of their salts, including those saltsthat can be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the freecompounds hereinbefore and hereinafter is to be understood as referringalso to the corresponding salts, as appropriate and expedient.

[0060] The compounds of formula I and N-oxides thereof have valuablepharmacological properties, as described hereinbefore and hereinafter.

[0061] The efficacy of the compounds of the invention as inhibitors ofVEGF-receptor tyrosine kinase activity can be demonstrated as follows:

[0062] Test for activity against VEGF-receptor tyrosine kinase. The testis conducted using Flt-1 VEGF-receptor tyrosine kinase. The detailedprocedure is as follows: 30 μl kinase solution (10 ng of the kinasedomain of Flt-1, Shibuya et al., Oncogene 5, 519-24 [1990]) in 20 mMTris.HCl pH 7.5, 3 mM manganese dichloride (MnCl₂), 3 mM magnesiumchloride (MgCl₂), 10 μM sodium vanadate, 0.25 mg/ml polyethylenglycol(PEG) 20000, 1 mM dithiothreitol and 3 μg/μl poly(Glu,Tyr) 4:1 (Sigma,Buchs, Switzerland), 8 μM [³³P]-ATP (0.2 μCi) ,1% dimethyl sulfoxide,and 0 to 100 μM of the compound to be tested are incubated together for10 minutes at room temperature. The reaction is then terminated by theaddition of 10 μl 0.25 M ethylenediaminetetraacetate (EDTA) pH 7. Usinga multichannel dispenser (LAB SYSTEMS, USA), an aliquot of 20 )l isapplied to a PVDF (=polyvinyl difluoride) Immobilon P membrane(Millipore, USA), through a Millipore microtiter filter manifold andconnected to a vacuum. Following complete elimination of the liquid, themembrane is washed 4 times successively in a bath containing 0.5%phosphoric acid (H₃PO₄) and once with ethanol, incubated for 10 minuteseach time while shaking, then mounted in a Hewlett Packard TopCountManifold and the radioactivity measured after the addition of 10 μlMicroscint® (β-scintillation counter liquid). IC₅₀-values are determinedby linear regression analysis of the percentages for the inhibition ofeach compound in three concentrations (as a rule 0.01, 0.1, and 1 μmol).The IC₅₀-values that can be found with compounds of formula I are in therange of 0.01 to 100 μM, preferably in the range from 0.01 to 50 μM.

[0063] The antitumor efficacy of the compounds of the invention can bedemonstrated in vivo as follows:

[0064] In vivo activity in the nude mouse xenotransplant model: femaleBALB/c nude mice (8-12 weeks old), Novartis Animal Farm, Sisseln,Switzerland) are kept under sterile conditions with water and feed adlibitum. Tumors are induced either by subcutaneous injection of tumorcells into mice (for example, Du 145 prostate carcinoma cell line (ATCCNo. HTB 81; see Cancer Research 37, 4049-58 (1978)) or by implantingtumor fragments (about 25 mg) subcutaneously into the left flank of miceusing a 13-gauge trocar needle under Forene® anaesthesia (Abbott,Switzerland). Treatment with the test compound is started as soon as thetumor has reached a mean volume of 100 mm³. Tumor growth is measured twoto three times a week and 24 hours after the last treatment bydetermining the length of two perpendicular axes. The tumor volumes arecalculated in accordance with published methods (see Evans et al., Brit.J. Cancer 45, 466-8 [1982]). The antitumor efficacy is determined as themean increase in tumor volume of the treated animals divided by the meanincrease in tumor volume of the untreated animals (controls) and, aftermultiplication by 100, is expressed as T/C %. Tumor regression (given in%) is reported as the smallest mean tumor volume in relation to the meantumor volume at the start of treatment. The test compound isadministered daily by gavage.

[0065] As an alternative other cell lines may also be used in the samemanner, for example:

[0066] the MCF-7 breast adenocarcinoma cell line (ATCC No. HTB 22; seealso J. Natl. Cancer Inst. (Bethesda) 51, 1409-16 [19731);

[0067] the MDA-MB 468 breast adenocarcinoma cell line (ATCC No. HTB 132;see also In Vitro 14, 911-15 [1978]);

[0068] the MDA-MB 231 breast adenocarcinoma cell line (ATCC No. HTB 26;see also J. Natl. Cancer Inst. (Bethesda) 53, 661-74 [1974]);

[0069] the Colo 205 colon carcinoma cell line (ATCC No. CCL 222; seealso Cancer Res. 38, 1345-55 [1978]);

[0070] the HCT 116 colon carcinoma cell line (ATCC No. CCL 247; see alsoCancer Res. 41, 1751-6 (1981]);

[0071] the DU145 prostate carcinoma cell line DU 145 (ATCC No. HTB 81;see also Cancer Res. 37, 4049-58 [1978]); and

[0072] the PC-3 prostate carcinoma cell line PC-3 (ATCC No. CRL 1435;see also Cancer Res. 40, 524-34 [1980]).

[0073] The inhibition of VEGF-induced KDR-receptor autophosphorylationcan be confirmed wit a further in vitro experiment in cells: transfectedCHO cells, which permanently express human VEGF receptor (KDR), areseeded in complete culture medium (with 10% fetal calf serum=FCS) in6-well cell-culture plates and incubated at 37° C. under 5% CO₂ untilthey show about 80% confluency. The compounds to be tested are thendiluted in culture medium (without FCS, with 0.1% bovine serum albumin)and added to the cells. (Controls comprise medium without testcompounds). After two hours' incubation at 37° C., recombinant VEGF isadded; the final VEGF concentration is 20 ng/ml). After a further fiveminutes' incubation at 37° C., the cells are washed twice with ice-coldPBS (phosphate-buffered saline) and immediately lysed in 100 μl lysisbuffer per well. The lysates are then centrifuged to remove the cellnuclei, and the protein concentrations of the supernatants aredetermined using a commercial protein assay (BIORAD). The lysates canthen either be immediately used or, if necessary, stored at −20° C.

[0074] A sandwich ELISA is carried out to measure the KDR-receptorphosphorylation: a monoclonal antibody to KDR (for example Mab1495.12.14; prepared by H. Towbin) is immobilized on black ELISA plates(OptiPlate™ HTRF-96 from Packard). The plates are then washed and theremaining free protein-binding sites are saturated with 1% BSA in PBS.The cell lysates (20 μg protein per well) are then incubated in theseplates overnight at 4° C. together with an antiphosphotyrosine antibodycoupled with alkaline phosphatase (PY20:AP from TransductionLaboratories). The (plates are washed again and the) binding of theantiphosphotyrosine antibody to the captured phosphorylated receptor isthen demonstrated using a luminescent AP substrate (CDP-Star, ready touse, with Emerald II; TROPIX). The luminescence is measured in a PackardTop Count Microplate Scintillation Counter (Top Count). The differencebetween the signal of the positive control (stimulated with VEGF) andthat of the negative control (not stimulated with VEGF) corresponds toVEGF-induced KDR-receptor phosphorylation (=100%). The activity of thetested substances is calculated as % inhibition of VEGF-inducedKDR-receptor phosphorylation, wherein the concentration of substancethat induces half the maximum inhibition is defined as the ED50(effective dose for 50% inhibition). Compounds of formula I herepreferably show ED50 values in the range of 0.001 μM to 6 μM, preferably0.005 to 0.5 μM.

[0075] A compound of formula I or a N-oxide thereof inhibits to varyingdegrees also other tyrosine kinases involved in signal transductionwhich are mediated by trophic factors, for example AbI kinase, kinasesfrom the Src family, especially c-Src kinase, Lck, and Fyn; also kinasesof the EGF family, for example, c-erbB2 kinase (HER-2), c-erbB3 kinase,c-erbB4 kinase; insulin-like growth factor receptor kinase (IGF-1kinase), especially members of the PDGF-receptor tyrosine kinase family,such as PDGF-receptor kinase, CSF-1-receptor kinase, Kit-receptor kinaseand VEGF-receptor kinase; and also serine/threonine kinases, all ofwhich play a role in growth regulation and transformation in mammaliancells, including human cells.

[0076] The inhibition of c-erbB2 tyrosine kinase (HER-2) can bemeasured, for example, in the same way as the inhibition of EGF-Rprotein kinase (see House et al., Europ. J. Biochem. 140, 363-7 [1984]).The erbB2 kinase can be isolated, and its activity determined, usingmethods known per se (see T. Akiyama et al., Science 232, 1644 [1986]).

[0077] On the basis of these studies, a compound of formula I accordingto the invention shows therapeutic efficacy especially against disordersdependent on protein kinase, especially proliferative diseases.

[0078] The usefulness of a compound of the formula I in the treatment ofarthritis as an example of an inflammatory rheumatic or rheumatoiddisease can be demonstrated as follows:

[0079] The well-known rat adjuvant arthritis model (Pearson, Proc. Soc.Exp. Biol. 91, 95-101 (1956)) is used to test the anti-arthriticactivity of compounds of the formula I, or salts thereof. AdjuvantArthritis can be treated using two different dosing schedules: either(i) starting time of immunisation with adjuvant (prophylactic dosing);or from day 15 when the arthritic response is already established(therapeutic dosing). Preferably a therapeutic dosing schedule is used.For comparison, a cyclooxygenase-2 inhibitor, such as5-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene ordiclofenac, is administered in a separate group.

[0080] In detail, male Wistar rats (5 animals per group, weighingepproximately 200 g, supplied by Iffa Credo, France) are injected i.d.(intra-dermally) at the base of the tail with 0.1 ml of mineral oilcontaining 0.6 mg of lyophilised heat-killed Mycobacterium tuberculosis.The rats are treated with the test compound (3, 10 or 30 mg/kg p.o. onceper day), or vehicle (water) from day 15 to day 22 (therapeutic dosingschedule). At the end of the experiment, the swelling of the tarsaljoints is measured by means of a mico-calliper. Percentage inhibition ofpaw swelling is calculated by reference to vehicle treated arthriticanimals (0% inhibition) and vehicle treated normal animals (100%inhibition).

[0081] The activity of compounds of the formula I against pain can beshown in the following model of nociception (pain). In this model, thehyperalgesia caused by an intra-planar yeast injection is measured byapplying increased pressure to the foot until the animal vocalizes orwithdraws its foot from the applied pressure pad. The model is sensitiveto COX inhibitors, and diclofenac at 3 mg/kg is used as a positivecontrol.

[0082] Method: The baseline pressure required to induce vocalization orwithdrawal of the paw of male Sprague Dawley rats (weighingapproximately 180 g, supplied by Iffa Credo, France) is measured (2hours before treatment), followed by an intra-planar injection of 100 μlof a 20% yeast suspension in water in the hind paw. The rats are treatedorally with the test compound (3, 1 0 or 30 mg/kg), diclofenac (3 mg/kg)or vehicle (saline) p.o. 2 hours later (time point 0 hours), and thepressure test is repeated 1 and 2 hours after dosing. Using the standardapparatus supplied by Ugo Basile, Italy, the pressure required to inducevocalisation or paw withdrawal of the compound-treated rats at thesetime points is compared to that of vehicle-treated animals.

[0083] On the basis of these studies, a compound of formula Isurprisingly is appropriate for the treatment of inflammatory(especially rheumatic or rheumatoid) diseases and/or pain. The compoundsof the formula 1, especially IA, (or an N-oxide thereof) according tothe invention also show therapeutic efficacy especially against otherdisorders dependent on protein kinase, especially proliferativediseases.

[0084] On the basis of their efficacy as inhibitors of VEGF-receptortyrosine kinase activity, the compounds of the formula I primarilyinhibit the growth of blood vessels and are thus, for example, effectiveagainst a number of diseases associated with deregulated angiogenesis,especially diseases caused by ocular neovascularisation, especiallyretinopathies, such as diabetic retinopathy or age-related maculadegeneration, psoriasis, haemangioblastoma, such as haemangioma,mesangial cell proliferative disorders, such as chronic or acute renaldiseases, e.g. diabetic nephropathy, malignant nephrosclerosis,thrombotic microangiopathy syndromes or transplant rejection, orespecially inflammatory renal disease, such as glomerulonephritis,especially mesangioproliferative glomerulonephritis, haemolytic-uraemicsyndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma,arterial restenosis, autoimmune diseases, acute inflammation, fibroticdisorders (e.g. hepatic cirrhosis), diabetes, endometriosis, chronicasthma, arterial or post-transplantational atherosclerosis,neurodegenerative disorders and especially neoplastic diseases (solidtumours, but also leucemias and other “liquid tumours”, especially thoseexpressing c-kit, KDR or flt-1), such as especially breast cancer,cancer of the colon, lung cancer (especially small-cell lung cancer),cancer of the prostate or Kaposi's sarcoma. A compound of formula I (oran N-oxide thereof) inhibits the growth of tumours and is especiallysuited to preventing the metastatic spread of tumours and the growth ofmicrometastases.

[0085] A compound of formula I can be administered alone or incombination with one or more other therapeutic agents, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic agents being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic agents. A compound of formula I can besides or inaddition be administered especially for tumor therapy in combinationwith chemotherapy, radiotherapy, immunotherapy, surgical intervention,or a combination of these. Long-term therapy is equally possible as isadjuvant therapy in the context of other treatment strategies, asdescribed above. Other possible treatments are therapy to maintain thepatient's status after tumor regression, or even chemopreventivetherapy, for example in patients at risk.

[0086] Therapeutic agents for possible combination are especially one ormore cytostatic or cytotoxic compounds, for example a chemotherapeuticagent or several selected from the group comprising an inhibitor ofpolyamine biosynthesis, an inhibitor of protein kinase, especially ofserine/threonine protein kinase, such as protein kinase C, or oftyrosine protein kinase, such as epidermal growth factor receptortyrosine kinase, a cytokine, a negative growth regulator, such as TGF-βor IFN-β, an aromatase inhibitor, a classical cytostatic, and aninhibitor of the interaction of an SH2 domain with a phosphorylatedprotein.

[0087] A compound according to the invention is not only for the(prophylactic and preferably therapeutic) management of humans, but alsofor the treatment of other warm-blooded animals, for example ofcommercially useful animals, for example rodents, such as mice, rabbitsor rats, or guinea-pigs. Such a compound may also be used as a referencestandard in the test systems described above to permit a comparison withother compounds.

[0088] In general, the invention relates also to the use of a compoundof formula I or a N-oxide thereof for the inhibition of VEGF-receptortyrosine activity, either in vitro or in vivo.

[0089] A compound of formula I or a N-oxide thereof may also be used fordiagnostic purposes, for example with tumors that have been obtainedfrom warm-blooded animal “hosts”, especially humans, and implanted intomice to test them for decreases in growth after treatment with such acompound, in order to investigate their sensitivity to the said compoundand thus to improve the detection and determination of possibletherapeutic methods for neoplastic diseases in the original host.

[0090] With the groups of preferred compounds of formula I and N-oxidesthereof mentioned hereinafter, definitions of substituents from thegeneral definitions mentioned hereinbefore may reasonably be used, forexample, to replace more general definitions with more specificdefinitions or especially with definitions characterized as beingpreferred;

[0091] Furthermore, the invention relates to the use of a compound offormula I, wherein the radicals and symbols have the meanings as definedabove, or a N-oxide or a pharmaceutically acceptable salt thereof forthe preparation of a pharmaceutical product for the treatment ofretinopathy or age-related macula degeneration.

[0092] Furthermore, the invention relates to a method for the treatmentof a neoplastic disease which responds to an inhibition of theVEGF-receptor tyrosine kinase activity, which comprises administering acompound of formula I or a N-oxide or a pharmaceutically acceptable saltthereof, wherein the radicals and symbols have the meanings as definedabove, in a quantity effective against the said disease, to awarm-blooded animal requiring such treatment.

[0093] Furthermore, the invention relates to a method for the treatmentof retinopathy or age-related macular degeneration, which comprisesadministering a compound of formula I or a N-oxide or a pharmaceuticallyacceptable salt thereof, wherein the radicals and symbols have themeanings as defined above, in a quantity effective against saiddiseases, to a warm-blooded animal requiring such treatment Theinvention relates in particular to a compound of formula 1, wherein

[0094] W is O or S;

[0095] X is NR₈;

[0096] Y is CR₉R₁₀-(CH₂)_(n) wherein

[0097] R₉ and R₁₀ are independently of each other hydrogen or loweralkyl, and

[0098] n is an integer of from and including 0 to and including 3; or

[0099] Y is SO₂;

[0100] R₁ is aryl;

[0101] R₂ is a mono- or bicyclic heteroaryl group comprising one or morering nitrogen atoms with the exception that R₂ cannot represent2-phthalimidyl, and in case of Y═SO₂ cannot represent2,1,3-benzothiadiazol-4-yl;

[0102] any of R₃, R₄, R₅ and R₆, independently of the other, is H or asubstituent other than hydrogen; and

[0103] R₇ and R₈, independently of each other, are H or lower alkyl;

[0104] with the exception of the compound of formula I wherein W is O, Xis NR₈, Y is CH₂, R₁ is 4-chlorophenyl, R₂ is 2-pyridyl, R₃, R₄, R₅, R₇and R₈ are each H and R₆ is chloro;

[0105] or a N-oxide or a pharmaceutically acceptable salt thereof.

[0106] Preferred are compounds of formula I, wherein

[0107] W is O or S;

[0108] X is NR₈;

[0109] Y is CHR₉-(CH₂)_(n) wherein

[0110] R₉ is hydrogen or lower alkyl, and

[0111] n is an integer of from and including 0 to and including 3; or

[0112] Y is SO₂;

[0113] R₁ is aryl;

[0114] R₂ is a mono- or bicyclic heteroaryl group comprising one or morering nitrogen atoms with the exception that R₂ cannot represent2-phthalimidyl, and in case of Y═SO₂ cannot represent2,1,3-benzothiadiazol-4-yl;

[0115] any of R₃, R₄, R₅ and R₆, independently of the other, is H or asubstituent other than hydrogen; and

[0116] R₇ and R₈, independently of each other, are H or lower alkyl;

[0117] with the exception of the compound of formula I wherein W is 0, Xis NR₈, Y is CH₂, R₁ is 4-chlorophenyl, R₂ is 2-pyridyl, R₃, R₄, R₅, R₇and R₈ are each H and R₆ is chloro;

[0118] or a salt thereof.

[0119] In particular, preferred compounds of formula I are those inwhich

[0120] W is O or S;

[0121] X is NR₈;

[0122] Y is CHR₉-(CH₂)_(n) wherein

[0123] R₉ is H or lower alkyl, and

[0124] n is 0 to 3; or

[0125] Y is SO₂;

[0126] R₁ is phenyl that is unsubsituted or substituted by up to threesubstituents selected from amino, mono- or disubstituted amino whereinthe substituents are selected independently from lower alkyl,hydroxy-lower alkyl, phenyl-lower alkyl, lower alkanoyl, benzoyl andsubstituted benzoyl wherein the phenyl radical is substituted by one ortwo substituents selected from nitro, amino, halogen, N-loweralkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy,lower-alkoxycarbonyl, lower alkanoyl and carbamoyl, and phenyl-loweralkoxycarbonyl wherein the phenyl radical radical is substituted by oneor two substituents selected from nitro, amino, halogen, N-loweralkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy,lower-alkoxycarbonyl, lower alkanoyl and carbamoyl; lower alkyl;substituted lower alkyl where up to three substituents are presentindependently selected from the group containing halogen, N-loweralkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, hydroxy,cyano, carboxy, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl;hydroxy, lower alkoxy; phenyl-lower alkoxy; phenyloxy; halogen-loweralkoxy, lower alkanoyloxy; benzoyloxy; lower alkoxycarbonyloxy;phenyl-lower alkoxycarbonyloxy; nitro; cyano; carboxy; loweralkoxycarbonyl; phenyl-lower alkoxycarbonyl; phenyloxycarbonyl; loweralkylcarbonyl; carbamoyl; N-mono- or N,N-disubstituted carbamoyl that issubstituted by one or two substituents independently selected from loweralkyl, phenyl-lower alkyl and hydroxy-lower alkyl, at the terminalnitrogen atom; amidino; guanidino; mercapto; sulfo; lower alkylthio;phenylthio; phenyl-lower alkylthio; lower alkylphenylthio; loweralkylsulfinyl; phenylsulfinyl; phenyl-lower alkylsulfinyl; loweralkylphenylsulfinyl; lower alkanesulfonyl; phenylsulfonyl; phenyl-loweralkylsulfonyl; lower alkylphenylsulfonyl; lower alkenyl; lower alkanoyl;halogen-lower alkylmercapto; halogen-lower alkylsulfonyl; dihydroxybora(-B(OH)₂); and lower alkylene dioxy bound at adjacent C-atoms of thering;

[0127] R₂ is imidazolyl, quinolyl, naphthyridinyl, or a moiety of theformula Ib or Ic

[0128] wherein

[0129] r is 0 to 2;

[0130] A, B, D, and E are, independently of one another, N or CH, withthe stipulation that not more than 2 of these radicals are N;preferably; and

[0131] Q is lower alkyl, hydroxy, lower alkoxy, lower thioalkyl orhalogen;

[0132] any of R₃, R₄, R₅ and R₆, independently of the other, is H,fluorine or lower alkyl; and

[0133] R₇ and R₈, independently of each other, are H or lower alkyl;

[0134] or a N-oxide or a pharmaceutically acceptable salt thereof.

[0135] More specifically, preference is given to a compound of formulaI, wherein

[0136] W is O;

[0137] X is NR₈;

[0138] Y is CHR₉-(CH₂)_(n) wherein

[0139] R₉ is H or methyl, and

[0140] n is 0;

[0141] or Y is SO₂;

[0142] R₁ is phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl which is ineach case either unsubsituted or independently substituted by one or twosubstituents selected from the group comprising halogen; lower alkyl;lower alkoxy; hydroxy; phenyl; phenoxy; halogen-lower alkoxy;halogen-lower alkyl; lower alkoxycarbonyl; N-lower alkyl carbamoyl;lower alkylsulfinyl; lower alkanesulfonyl; and lower alkoxycarbonyllower alkyl;

[0143] R₂ is imidazolyl, quinolyl, naphthyridinyl,2-methyl-pyridin-4-yl, 3-pyridyl or 4-pyridyl; any of R₃, R₄, R₅ and R₆,independently of the other, are H, methyl or chloro; or

[0144] R₃ and R₄ together represent methylene dioxy and R₅ and R₆,independently of the other, are H, methyl or chloro; and

[0145] R₇ and R₈, independently of each other, are H, fluorine ormethyl;

[0146] or a N-oxide or a pharmaceutically acceptable salt thereof.

[0147] Even more specifically, preference is given to a compound offormula I, wherein

[0148] W is O;

[0149] X is NR₈

[0150] Y is CHR₉-(CH₂)_(n) wherein

[0151] R₉ is H or methyl, and

[0152] n is 0;

[0153] or Y is SO₂;

[0154] R₁ is phenyl which is either unsubstituted or independentlysubstituted by one or two substituents selected from the groupcomprising halogen; lower alkyl; halogen-lower alkyl; loweralkylsulfinyl; and lower alkanesulfonyl;

[0155] R₂ is imidazolyl, quinolyl, naphthyridinyl,2-methyl-pyridin-4-yl, 3-pyridyl or 4-pyridyl;

[0156] any of R₃, R₄, R₅ and R₆, independently of the other, is H ormethyl; and

[0157] R₇ and R₈, independently of each other, are H or methyl;

[0158] or a N-oxide or a pharmaceutically acceptable salt thereof.

[0159] Mostly preferred are compounds of formula I wherein

[0160] W is O;

[0161] X is NR₈

[0162] Y is CHR₉-(CH₂)_(n) wherein

[0163] R₉ is H or methyl, and

[0164] n is 0;

[0165] or Y is SO₂;

[0166] R₁ is phenyl which is either unsubstituted or independentlysubstituted by one or two substituents selected from the groupcomprising halogen; lower alkyl; halogen-lower alkyl; loweralkylsulfinyl; and lower alkanesulfonyl;

[0167] R₂ is imidazolyl, quinolyl, 2-methyl-pyridin-4-yl or 4-pyridyl;

[0168] any of R₃, R₄, R₅ and R₆, independently of the other, is H ormethyl; and

[0169] R₇ and R₈, independently of each other, are H or methyl;

[0170] or a salt thereof.

[0171] Especially preferred are compounds of formula I wherein

[0172] W is O;

[0173] X is NR₈;

[0174] Y is CH₂;

[0175]₁ is phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl which is ineach case either unsubstituted or independently substituted by one ortwo substituents selected from the group comprising halogen; loweralkyl; lower alkoxy; hydroxy; phenyl; phenoxy; halogen-lower alkoxy;lower alkoxycarbonyl; N-lower alkyl carbamoyl; and lower alkoxycarbonyllower alkyl;

[0176] R₂ is 4-pyridyl;

[0177] any of R₃, R₄, R₅ and R₆, independently of the other, are H,methyl or chloro; or

[0178] R₃ and R₄ together represent methylene dioxy and R₅ and R₆,independently of the other, are H, methyl or chloro; and

[0179] R₇ and R₈ are H;

[0180] or a N-oxide or a pharmaceutically acceptable salt thereof.

[0181] More special preference is given to a compound of formula I suchas is mentioned in the Examples below, or a pharmaceutically acceptablesalt thereof, especially a compound of the formula I or a salt thereofspecifically mentioned in the Examples.

[0182] High preference is given to a compound selected from

[0183] 2-[(4-pyridyl)methyl]amino-N-(4-trifluoromethylphenyl)benzamide;

[0184] 2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

[0185] 2-[(4-pyridyl)methyl]amino-N-(4-methylphenyl)benzamide;

[0186] 2-[(4-pyridyl)methyl]amino-N-(3-fluoro-4-methylphenyl)benzamide;

[0187]2-[(4-pyridyl)methyl]amino-N-(4-chloro-3-trifluoromethylphenyl)benzamide;

[0188]2-[(4-pyridyl)methyl]amino-N-(3chloro-5-trifluoromethylphenyl)benzamide;

[0189] 2-[(4-pyridyl)methyl]amino-N-(4-methylphenyl)-6-methylbenzamide;and

[0190] 2-[(4-quinolyl)methyl]amino-N-(4-chlorophenyl)benzamide;

[0191] or a pharmaceutically acceptable salt thereof.

[0192] Furthermore, high preference is given to a compound selected from

[0193]2-[(4-pyridyl)methyl]amino-N-(3-fluoro-(4-trifluoromethyl)phenyl]benzamide;

[0194] 2-1(4-pyridyl)methyl]amino-N-phenylbenzamide;

[0195]2-[(4-pyridyl)methyl]amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]benzamide;

[0196]2-[(4-pyridyl)methyl]amino-N-[3-fluoro-5-(trifluoromethyl)phenyl]benzamide;

[0197]2-[(4-pyridyl)methyl]amino-N-[3,5-(bistrifluoromethyl)phenyl]benzamide;

[0198]2-[(4-pyridyl)methyl]amino-N-[3,4-bis-(trifluoromethyl)phenyl]benzamide;

[0199]2-[(4-pyridyl)methyl]amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide;

[0200]2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0201]2-[(4-pyridyl)methyl]amino-N-[3-(1,1-dimethylethyl)phenyl]benzamide;

[0202] 2-[(4-pyridyl)methyl]amino-N(3-cyanophenyl)benzamide;

[0203] 2-[(4-pyridyl)methyl]amino-N-[(3-methylthio)phenyl]benzamide;

[0204] 2-[(4-pyridyl)methyl]amino-N-(3-acetylaminophenyl)benzamide;

[0205]2-[(4-pyridyl)methyl]amino-N-[3-1(aminocarbonyl)amino]phenylbenzamide;

[0206] 2-[(4-pyridyl)methylamino-N-[3-(dimethylamino)phenyl]benzamide;

[0207]5-methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0208]3-methyl-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0209]4,5-difluoro-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenylbenzamide;

[0210]2-[(4-pyridyl)methyl]amino-N-methyl-N-[3-(trifluoromethyl)phenyl]benzamide;

[0211]2-[(4-pyridyl)methyl]amino-N-1(3-methylsulphonyl)phenyl)benzamide;

[0212] 2-[(4-pyridyl)methyl]amino-N-[(3-methylsulphinylphenyl]benzamide;

[0213]2-[(4-pyridyl)methyl]amino-N-[4-(1,1-dimethylethyl)phenyl]benzamide;

[0214] 2-[(4-pyridyl)methyl]amino-N(3-chlorophenyl)benzamide;

[0215] 2-[(4-pyridyl)methyl]amino-N(3-bromophenyl)benzamide;

[0216] 2-[(4-pyridyl)methyl]amino-(3-methylphenyl)benzamide;

[0217] 2-[(4-pyridyl)methyl]amino-N(3-benzoylphenyl)benzamide;

[0218] 2-[(4-pyridyl)methyl]amino-N-3-(aminocarbonyl)phenyl]benzamide;

[0219]2-[(3-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0220]2-[(4-quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0221]2-[(5-quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0222]2-[(4-(2-methyl)pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0223]2-1(4(1,2dihydro-2-oxo)pyridyl)methylamino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0224] 2-1(4-quinolinyl)methylamino-N-(4-chlorophenyl)benzamide;

[0225] 2-1(2-imidazolyl)methyl]amino-N-(4-chlorophenyl)benzamide;

[0226]2-[2-(4-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0227]2-[2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0228]2-[1-methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0229]2-[(1-oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;and

[0230]2-1(4-pyridyl)methyl]methylamino-N-[3-(trifluoromethyl)phenyl]benzamide;

[0231] 2-[(4-pyridyl)methyl]amino-N-(4-chloronaphthyl)benzamide;

[0232] 6-methyl-2-[(4-pyridyl)methyl]amino-AL(4-chlorophenyl)benzamide;

[0233] 6-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

[0234]3,4-methylendioxy-6-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

[0235]4,5-dimethyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

[0236]5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;

[0237] 2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;

[0238] 2-[(4-pyridyl)methyl]amino-N-(7-hydroxynaphthyl)benzamide;

[0239] 2-[(4-pyridyl)methyl]amino-N-(8-hydroxy-2-naphthyl)benzamide;4-chloro-2-.(4pyridyl)methyl]amino-N-(4chlorophenyl)benzamide;

[0240] 5-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

[0241]2-[(4-pyridyl)methyl]amino-N-(5,6,7,8tetrahydronaphthyl)benzamide;

[0242] 2-[(4-pyridyl)methyl amino-N-(4-biphenyl)benzamide;

[0243] 5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

[0244] 2-[(4-pyridyl)methyl]amino-N-(naphthyl)benzamide;

[0245] 2-[(4-pyridyl)methyl]amino-N-(2-napthyl)benzamide;

[0246] 2-[(4-pyridyl)methyl]amino-N-(4-methoxyphenyl)benzamide;

[0247]2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethoxy)phenyl]benzamide;

[0248] 2-[(4-pyridyl)methyl]amino-N-(4-methoxy-2-naphthyl)benzamide;

[0249] 2-[(4-pyridyl)methyl]amino-N-(3-bromo-2-naphthyl)benzamide;

[0250]2-[(4-pyridyl)methyl]amino-N-[4-(isopropoxycarbonyl)phenyl]benzamide;

[0251]2-[(4-pyridyl)methyl]amino-N-[4-(trifluoromethoxy)phenyl]benzamide;

[0252]2-[(4-pyridyl)methyl]amino-N-[4-(isopropylcarbamoyl)phenyl]benzamide;

[0253] 2-[(4-pyridyl)methyl]amino-N-(3-chloro-4-methylphenyl)benzamide;

[0254] 2-[(4-pyridyl)methyl]amino-N-(2-methylphenyl)benzamide;

[0255]2-1(4-pyridyl)methyl]amino-N-[3-(methoxycarbonylmethyl)phenyl]benzamide;

[0256] 2-[(4-pyridyl)methylamino-N-(4-phenoxyphenyl)benzamide;

[0257] or a pharmaceutically acceptable salt thereof.

[0258] A compound of the invention may be prepared by processes that,though not applied hitherto for the new compounds of the presentinvention, are known per se, especially a process characterized in that

[0259] a) for the synthesis of a compound of the formula I wherein Xrepresents NR₈, where R₈ is hydrogen and Y represents CHR₉-(CH₂)1, eachas indicated for a compound of formula I, and the remaining symbols R₁,R₂, R₃, R₄, R₅ and R₆ are as defined for a compound of the formula I, ananiline derivative of the formula II

[0260] wherein W, R₁, R₃, R₄, R₅, R₆ and R₇ are as defined for acompound of the formula I, is reacted with a carbonyl compound of theformula III

R₂-(CH₂)_(n)-C(R₉)═O   (III)

[0261] wherein n, R₂ and R₉ are as defined for a compound of the formulaI in the presence of a reducing agent; or

[0262] b) for the synthesis of a compound of the formula I wherein Y isSO₂ and the remaining symbols R₁, R₂, R₃, R₄, R₅, R₆, R₇, W and X are asdefined for a compound of the formula I, an aniline derivative of theformula II as defined under process variante a) is reacted with an acidof the formula IVa

R₂-Y—OH   (IVa)

[0263] or a reactive derivative thereof; or with a compound of formulaIVb,

R₂-Y-Hal′  (IVb)

[0264] wherein Hal′ is chloro, bromo or iodo; or

[0265] c) for the synthesis of compounds of the formula I wherein Xrepresents NR₈, Y represents CR₉R₁₀(CH₂)n and the remaining symbols R₁,R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined for a compound of theformula I, a halogen derivative of the formula V.

[0266] wherein Hal represents iodine, bromine or chlorine and W, R₁, R₃,R₄, R₅, R₆ and R₇ are as defined for a compound of the formula I, isreacted with an amine of the formula VI

R₂-(CH₂)_(n)-C(R₉)(R₁₀)—NHR₈   (VI)

[0267] wherein n, R₂, R₈, R₉ and R₁₀ are as defined for a compound ofthe formula I in the presence of an appropriate catalyst such as apalladium catalyst, for example as generated in situ fromtris(dibenzylideneacetone)-dipalladium[0] and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl in an inert solvent such astoluene, in the presence of an aprotic base such as sodium t-butoxide orcaesium carbonate, or a nickel catalyst, such asdibromobis(bipyridyl)-nickel[2] in a sovent such as isopropylmethylketone, or a copper catalyst, such as copper(l)iodide in a solvent suchas dimethylformamide;

[0268] d) for the synthesis of compounds of the formula I wherein Xrepresents NR₈, Y represents CH₂, W is 0, R₂ is 4-pyridyl, R₇ and R₈ areeach H and and R₁, R₃, R₄, R₅ and R₆ are as defined for a compound ofthe formula I, a compound of formula VII

[0269] wherein R₃, R₄, R₅ and R₆ are as defined for a compound of theformula I and R₁, is lower alkyl, is reacted with a compound of formulaVIII

H₂NR₁   (VIII)

[0270] wherein R₁ is as defined for a compound of formula I in thepresence of trimethylaluminium in an inert solvent, e.g. toluol;

[0271] where the starting compounds defined in a), b), c) or d) may alsobe present with functional groups in protected form if necessary and/orin the form of salts, provided a salt-forming group is present and thereaction in salt form is possible;

[0272] any protecting groups in a protected derivative of a compound ofthe formula I are removed;

[0273] and, if so desired, an obtainable compound of formula I isconverted into another compound of formula I or a N-oxide thereof, afree compound of formula I is converted into a salt, an obtainable saltof a compound of formula I is converted into the free compound oranother salt, and/or a mixture of isomeric compounds of formula I isseparated into the individual isomers.

[0274] Detailed description of the process variants:

[0275] In the more detailed description of the process below, R₁, R₂,R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ X, Y and W are as defined for compoundsof formula I, unless otherwise indicated.

[0276] Process a) (reductive alkylation)

[0277] The carbonyl compound of the formula III may also be present inthe form of reactive derivative; however, the free aldehyde or ketone ispreferred.

[0278] Reactive derivatives of the compounds of formula III are, forexample, corresponding bisulfite adducts or especially semiacetals,acetals, semiketals or ketals of compounds of formula III with alcohols,for example lower alkanols; or thioacetals or thioketals of compounds offormula III with mercaptans, for example lower alkanesulfides.

[0279] The reductive alkylation is preferably carried out withhydrogenation in the presence of a catalyst, especially a noble metalcatalyst, such as platinum or especially palladium, which is preferablybonded to a carrier material, such as carbon, or a heavy metal catalyst,such as Raney nickel, at normal pressure or at pressures of from 0.1 to10 MegaPascal (MPa), or with reduction by means of complex hydrides,such as borohydrides, especially alkali metal cyanoborohydrides, forexample sodium cyanoborohydride, in the presence of a suitable acid,preferably relatively weak acids, such as lower alkanecarboxylic acids,especially acetic acid, or a sulfonic acid, such as p-toluenesulfonicacid; in customary solvents, for example alcohols, such as methanol orethanol, or ethers, for example cyclic ethers, such as tetrahydrofuran,in the presence or absence of water.

[0280] Process b) (condensation)

[0281] In this process the reagents introducing the radical R₂Y— containeither a free sulfo group (formula IVa) or are in the form of a reactivederivative thereof, for example in the form of a derived activated esteror reactive anhydride, or in the form of a reactive cyclic amide, orcontain the sulfo group in the form of a sulfonic acid halide (formulaIVb). Reactive derivatives may also be formed in situ.

[0282] In formula IVb Hal′ is preferably chlorine or bromine. Thereaction is carried out in a suitable solvent, e.g. dichloromethane,e.g. at room temperature or the reflux temperature of the solvent, inthe presence of a suitable amine, e.g. N-ethyldichlorophosphite, andoptionally 4-dimethylaminopyridine.

[0283] The amino group of compounds of formula II that participates inthe reaction preferably is in free form, especially when the sulfonylgroup reacting therewith is present in reactive form; it may, however,itself have been derivatised, for example by reaction with a phosphite,such as diethylchlorophosphite, 1,2-phenylene chlorophosphite,ethyldichlorophosphite, ethylene chlorophosphite ortetraethylpyrophosphite. A derivative of such a compound having an aminogroup is, for example, also a carbamic acid halide or an isocyanate, theamino group that participates in the reaction being substituted byhalocarbonyl, for example chlorocarbonyl, or modified in the form of anisocyanate group, respectively.

[0284] The condensation of activated esters, reactive anhydrides orreactive cyclic amides with the corresponding amines is customarilycarried out in the presence of an anorganic base, such as an alkalinemetal hydrogencarbonate of carbonate, or especially an organic base, forexample simple tri-lower alkylamines, for example triethylamine ortributylamine, or one of the above-mentioned organic bases. If desired,a condensation agent is additionally used, for example as described forfree carboxylic acids.

[0285] The condensation is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example formamide or dimethylformamide, ahalogenated hydrocarbon, for example methylene chloride, carbontetrachloride or chlorobenzene, a ketone, for example acetone, a cyclicether, for example tetrahydrofuran or dioxane, an ester, for exampleethyl acetate, or a nitrile, for example acetonitrile, or in a mixturethereof, as appropriate at reduced or elevated temperature, for examplein a temperature range of from approximately −40° to approximately +100°C., preferably from approximately −10° to approximately +70° C., andwhen arylsulfonyl esters are used also at approximately from +100° to+200° C., especially at temperatures of from 10° to 30° C., and ifnecessary under an inert gas atmosphere, for example a nitrogen or argonatmosphere.

[0286] Aqueous, for example alcoholic, solvents, for example ethanol, oraromatic solvents, for example benzene or toluene, may also be used.When alkali metal hydroxides are present as bases, acetone may also beadded where appropriate.

[0287] Process c) (amination)

[0288] The amination process is preferably carried out as an Ullmanntype reaction using a copper catalyst, such as copper[0] or a copper[I]compound such as copper[I]oxide, copper[I] bromide or copper[1]iodide inthe presence of a suitable base (such as a metal carbonate, for examplepotassium carbonate) to neutralise the acid generated in the reaction.This reaction is reviewed in Houben-Weyl “Methoden der OrganischenChemie”, Band 11/1, page 32-33. 1958, in Organic Reactions, Volume 14,page 19-24, 1965 and by J. Lindley (1984) in Tetrahedron, Volume 40,page 1433-1456. The amount of catalyst is typically in the range of 1 to20 mole percent. The reaction is carried out in an inert, aproticsolvent such as an ether (for example dimethoxyethane or dioxan) or anamide (for example dimethylformamide or N-methylpyrrolidone), under aninert atmosphere in the temperature range of 60-180° C.

[0289] An alternative amination process involves using a Group VIIIelement, where the metal core of the catalyst should be a zero-valenttransition metal, such as palladium or nickel, which has the ability toundergo oxidative addition to the Aryl-Halogen bond. The zero valentstate of the metal may be generated in situ from the N-[II] state. Thecatalyst complexes may include chelating ligands, such as alkyl, aryl orheteroaryl derivatives of phoshines or biphosphines, imines or arsines.Preferred cataysts contain palladium or nickel. Examples of suchcatalysts include palladium[II]chloride, palladium[II]acetate,tetrakis(triphenylphosphine)palladium[0] and nickel[II]acetylacetonate.The metal catayst is typically in the range of 0.1 to 10 mole percent.The chelating ligands may be either monodentate, as in the case forexample of trialkyphosphines, such as tributylphosphine, triarylphosphines, such as tri-(ortho-tolyl)phosphine, and triheteroarylphosphines, such as tri-2-furylphosphine; or they may be bidentate suchas in the case of 2,2′-bis9diphenylphosphino)-1,1′binaphthyl,1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferroceneand 1-(N,N-dimethyl-amino)-1′-(dicyclohexylphosphino)biphenyl. Thesupporting ligand may be added may be complexed to the metal centre inthe form of a metal complex prior to being added to the reaction mixtureor may be added to the reaction mixture as a separate compound. Thesupporting ligand is typically present in the range 0.01 to 20 molepercent It is often necessary to add a suitable base to the reactionmixture, such as a trialkylamine (for example diisoprpylethylamine or1,5-diazabicyclo[5,4,0]undec-5-ene), a Group I alkali metal alkoxide(for example potassium tertiary-butoxide) or carbonate (for examplecaesium carbonate) or potassium phosphate. The reaction is typicallycarried out in an inert aprotic solvent such as an ether (for exampledimethoxyethane or dioxan) or an amide (for example dimethylformamide orN-methylpyrrolidone), under an inert atmosphere in the temperature rangeof 60-180° C.

[0290] The amination Is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example dimethylformamide ordimethylacetamide, a cyclic ether, for example tetrahydrofuran ordioxane, or a nitrile, for example acetonitrile, or in a mixturethereof, at an appropriate temperature, for example in a temperaturerange of from approximately 40° to approximately 180° C., and ifnecessary under an inert gas atmosphere, for example a nitrogen or argonatmosphere.

[0291] Process d) (amidation)

[0292] In this process first a dimethylaluminium amide is prepared insitu from Me₃Al and an appropriate amine. Then the esters to be treatedare added and the reaction is carried out at a temperature between 20°C. and 150° C., preferably between 100° C. and 120° C., e.g. at 110° C.,depending on the reactivity of the amide and the ester, in an inertsolvent like benzene, toluene, xylene, tetrahydrofuran, C₆-C₁₀ alkanes,or a mixture thereof.

[0293] N-Oxides can be obtained in a known matter by reacting a compoundof formula I with hydrogen peroxide or a peracid, e.g.3-chloroperoxy-benzoic acid, in an inert solvent, e.g. dichloromethane,at a temperature between −10° C. and +35° C., e.g. 0° C. or roomtemperature.

[0294] Protecting groups

[0295] If one or more other functional groups, for example carboxy,hydroxy, amino, or mercapto, are or need to be protected in a compoundof formulae II, III and/or IV, because they should not take part in thereaction, these are such groups as are usually used in the synthesis ofpeptide compounds, and also of cephalosporins and penicillins, as wellas nucleic acid derivatives and sugars.

[0296] The protecting groups may already be present in precursors andshould protect the functional groups concerned against unwantedsecondary reactions, such as acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end-products.The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned hereinabove and hereinafter.

[0297] The protection of such functional groups by such protectinggroups, the protecting groups themselves, and their removal reactionsare described for example in standard reference works, such as J. F. W.McOmie, “Protective Groups in Organic Chemistry“, Plenum Press, Londonand New York 1973, in T. W. Greene, “Protective Groups in OrganicSynthesis”, Wiley, New York 1981, in “The Peptides”; Volume 3 (editors:E. Gross and J. Meienhofer), Academic Press, London and New York 1981,in “Methoden der organischen Chemie” (Methods of organic chemistry),Houben Weyl, 4th edition, Volume 15/l, Georg Thieme Verlag, Stuttgart1974, in H. -D. Jakubke and H. Jescheit, “Aminosäuren, Peptide,Proteine” (Amino acids, peptides, proteins), Verlag Chemie, Weinheim,Deerfield Beach, and Basel 1982, and in Jochen Lehmann, “Chemie derKohlenhydrate: Monosaccharide und Derivate” (Chemistry of carbohydrates:monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

[0298] Additional process steps

[0299] In the additional process steps, carried out as desired,functional groups of the starting compounds which should not take partin the reaction may be present in unprotected form or may be protectedfor example by one or more of the protecting groups mentionedhereinabove under “protecting groups”. The protecting groups are thenwholly or partly removed according to one of the methods describedthere.

[0300] Salts of a compound of formula I with a salt-forming group may beprepared in a manner known per se. Acid addition salts of compounds offormula I may thus be obtained by treatment with an acid or with asuitable anion exchange reagent. A salt with two acid molecules (forexample a dihalogenide of a compound of formula 1) may also be convertedinto a salt with one acid molecule per compound (for example amonohalogenide); this may be done by heating to a melt, or for exampleby heating as a solid under a high vacuum at elevated temperature, forexample from 130 to 170° C., one molecule of the acid being expelled permolecule of a compound of formula I.

[0301] Salts can usually be converted to free compounds, e.g. bytreating with suitable basic agents, for example with alkali metalcarbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides,typically potassium carbonate or sodium hydroxide.

[0302] Stereoisomeric mixtures, e.g. mixtures of diastereomers, can beseparated into their corresponding isomers in a manner known per se bymeans of suitable separation methods. Diastereomeric mixtures forexample may be separated into their individual diastereomers by means offractionated crystallization, chromatography, solvent distribution, andsimilar procedures. This separation may take place either at the levelof a starting compound or in a compound of formula I itself. Enantiomersmay be separated through the formation of diastereomeric salts, forexample by salt formation with an enantiomer-pure chiral acid, or bymeans of chromatography, for example by HPLC, using chromatographicsubstrates with chiral ligands.

[0303] A compound of formula I, wherein W is O, can be converted intothe respective compound wherein W is S, for example, by using anappropriate sulfur compound, e.g. using reaction with Lawesson's reagent(2,4-bis-(4-methoxyphenyl)2,4-dithioxo-1,2,3,4-dithiaphosphetan) in ahalogenated carbon hydrate, such as dichloromethane, or an aproticsolvent, such as toluene or xylene, at temperatures from about 30° C. toreflux.

[0304] A compound of the formula I wherein any one or both of R₇ and R₉is hydrogen and is part of a sulfonamide (Y is SO₂) bond can beconverted to the respective compound wherein R₇ and/or R₉ is lower alkylby reaction e.g. with a diazo lower alkyl compound, especiallydiazomethane, in an inert solvent, preferably in the presence of a noblemetal catalyst, especially in dispersed form, e.g. copper, or a noblemetal salt, e.g. cupper(I)-chloride or copper(II)-sulfate. Also reactionwith lower alkylhalogenides is possible, or with other leaving groupcarrying lower alkanes, e.g. lower alkyl alcohols esterified by a strongorganic sulfonic acid, such as a lower alkane sulfonic acid (optionallysubstituted by halogen, such as fluoro), an aromatic sulfonic acid, forexample unsubstituted or substituted benzene-sulfonic acid, thesubstituents preferably being selected from lower alkyl, such as methyl,halogen, such as bromo, and/or nitro, e.g. esterified by methanesulfonic acid, trimethane sulfonic acid or p-toluol sulfonic acid.

[0305] Also, in a compound of the formula I wherein R₈ is hydrogen and Yis CR₉R₁₀(CH₂)_(n), the alkylation may be made with such alkylatingagents.

[0306] In both cases, the alkylation takes place especially in aqueoussolution and/or in the presence of polar solvents, typically alcohols,for example methanol, ethanol, isopropanol, or ethylene glycol, ethers,typically dioxane, amides, typically dimethylformamide, or phenols,typically phenol, and also under non-aqueous conditions, in non-polarsolvents, typically benzene and toluene, or in benzene/water emulsions,where applicable in the presence of acidic or basic catalysts, forexample leaches, typically sodium hydroxide solution, or in the presenceof solid-phase catalysts, typically aluminium oxide, that have beendoped with hydrazine, in ethers, for example diethylether, generally attemperatures from about 0° C. to the boiling temperature of thecorresponding reaction mixture, preferably between 20° C. and refluxtemperature, if necessary under increased pressure, e.g. in a sealedtube, a temperature in excess of boiling point also being possible,and/or under inert gas, typically nitrogen or argon.

[0307] It should be emphasized that reactions analogous to theconversions mentioned in this chapter may also take place at the levelof appropriate intermediates.

[0308] General Process conditions

[0309] All process steps described here can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralisiing agents, for example ion exchangers, typically cationexchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to −60° C., at roomtemperature, at −20 to 40° C. or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder argon or nitrogen.

[0310] Salts may be present in all starting compounds and transients, ifthese contain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

[0311] At all reaction stages, isomeric mixtures that occur can beseparated into their individual isomers, e.g. diastereomers orenantiomers, or into any mixtures of isomers, e.g. racemates ordiastereomeric mixtures, typically as described under “Additionalprocess steps”.

[0312] In certain cases, typically in hydrogenation processes, it ispossible to achieve stereoselective reactions, allowing for exampleeasier recovery of individual isomers.

[0313] The solvents from which those can be selected which are suitablefor the reaction in question include for example water, esters,typically lower alkyl-lower alkanoates, e.g diethyl acetate, ethers,typically aliphatic ethers, e.g. diethylether, or cyclic ethers, e.g.tetrahydrofuran, liquid aromatic hydrocarbons, typically benzene ortoluene, alcohols, typically methanol, ethanol or 1- or 2-propanol,nitrites, typically acetonitrile, halogenated hydrocarbons, typicallydichloromethane, acid amides, typically dimethylformamide, bases,typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids,typically lower alkanecarboxylic acids, e.g. acetic acid, carboxylicacid anhydrides, typically lower alkane acid anhydrides, e.g. aceticanhydride, cyclic, linear, or branched hydrocarbons, typicallycyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g.aqueous solutions, unless otherwise stated in the description of theprocess. Such solvent mixtures may also be used in processing, forexample through chromatography or distribution.

[0314] The invention relates also to those forms of the process in whichone starts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described hereinabove as preferred, particularly as especiallypreferred, primarily preferred, and/or preferred above all.

[0315] In the preferred embodiment, a compound of formula I is preparedaccording to or in analogy to the processes and process steps defined inthe Examples.

[0316] The compounds of formula I, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallization (present as solvates).

[0317] Pharmaceutical preparations, methods, and uses

[0318] The present invention relates also to pharmaceutical compositionsthat comprise a compound of formula I or a N-oxide thereof as activeingredient and that can be used especially in the treatment of thediseases mentioned at the beginning. Compositions for enteraladministration, such as nasal, buccal, rectal or, especially, oraladministration, and for parenteral administration, such as intravenous,intramuscular or subcutaneous administration, to warm-blooded animals,especially humans, are especially preferred. The compositions comprisethe active ingredient alone or, preferably, together with apharmaceutically acceptable carrier. The dosage of the active ingredientdepends upon the disease to be treated and upon the species, its age,weight, and individual condition, the individual pharmacokinetic data,and the mode of administration.

[0319] The invention relates also to pharmaceutical compositions for usein a method for the prophylactic or especially therapeutic management ofthe human or animal body, to a process for the preparation thereof(especially in the form of compositions for the treatment of tumors) andto a method of treating tumor diseases, especially those mentionedhereinabove.

[0320] The invention relates also to processes and to the use ofcompounds of formula I or N-oxides thereof for the preparation ofpharmaceutical preparations which comprise compounds of formula I orN-oxides thereof as active component (active ingredient).

[0321] In the preferred embodiment, a pharmaceutical preparation issuitable for administration to a warm-blooded animal, especially humansor commercially useful mammals suffering from a disease responsive to aninhibition of angiogenesis or of VEGF-receptor tyrosine kinase, forexample psoriasis or especially a neoplastic disease, and comprises aneffective quantity of a compound of formula I or N-oxides thereof forthe inhibition of angiogenesis or of VEGF-receptor tyrosine kinase, or apharmaceutically acceptable salt thereof, if salt-forming groups arepresent, together with at least one pharmaceutically acceptable carrier.

[0322] A pharmaceutical composition for the prophylactic or especiallytherapeutic management of neoplastic and other proliferative diseases ofa warm-blooded animal, especially a human or a commercially usefulmammal requiring such treatment, especially suffering from such adisease, comprising as active ingredient in a quantity that isprophylactically or especially therapeutically active against the saiddiseases a novel compound of formula I or N-oxides thereof, is likewisepreferred.

[0323] The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active Ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories, or capsules. Further dosage forms are, for example,ointments, creams, pastes, foams, tinctures, lip-sticks, drops, sprays,dispersions, etc. Examples are capsules containing from about 0.05 g toabout 1.0 g active ingredient.

[0324] The pharmaceutical compositions of the present invention areprepared in a manner known per se, for example by means of conventionalmixing, granulating, coating, dissolving or lyophilizing processes.

[0325] Preference is given to the use of solutions of the activeingredient, and also suspensions or dispersions, especially isotonicaqueous solutions, dispersions or suspensions which, for example in thecase of lyophilized compositions comprising the active ingredient aloneor together with a carrier, for example mannitol, can be made up beforeuse. The pharmaceutical compositions may be sterilized and/or maycomprise excipients, for example preservatives, stabilizers, wettingagents and/or emulsifiers, solubilizers, salts for regulating osmoticpressure and/or buffers and are prepared in a manner known per se, forexample by means of conventional dissolving and lyophilizing processes.The said solutions or suspensions may comprise viscosity-increasingagents, typically sodium carboxymethylcellulose, carboxymethylcellulose,dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g.Tween 80® [polyoxyethylene(20)sorbitan mono-oleate; trademark of ICIAmericas, Inc, USA].

[0326] Suspensions in oil comprise as the oil component the vegetable,synthetic, or semi-synthetic oils customary for injection purposes. Inrespect of such, special mention may be made of liquid fatty acid estersthat contain as the acid component a long-chained fatty acid having from8 to 22, especially from 12 to 22, carbon atoms, for example lauricacid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid,margaric acid, stearic acid, arachidic acid, behenic acid orcorresponding unsaturated acids, for example oleic acid, elaidic acid,erucic acid, brassidic acid or linoleic acid, if desired with theaddition of antioxidants, for example vitamin E, β-carotene or3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fattyacid esters has a maximum of 6 carbon atoms and is a monovalent orpolyvalent, for example a mono-, di- or trivalent, alcohol, for examplemethanol, ethanol, propanol, butanol or pentanol or the isomers thereof,but especially glycol and glycerol. As fatty acid esters, therefore, thefollowing are mentioned: ethyl oleate, isopropyl myristate, isopropylpalmitate, “Labrafil M 2375” (polyoxyethylene glycerol trioleate fromGattefossé, Paris), “Labrafil M 1944 CS” (unsaturated polyglycolizedglycerides prepared by alcoholysis of apricot kernel oil and consistingof glycerides and polyethylene glycol ester; Gattefossé, France),“Labrasol” (saturated polyglycolized glycerides prepared by alcoholysisof TCM and consisting of glycerides and polyethylene glycol ester;Gattefossé, France), and/or “Miglyol 812” (triglyceride of saturatedfatty acids of chain length C₈ to C₁₂ from Hüls AG, Germany), butespecially vegetable oils such as cottonseed oil, almond oil, olive oil,castor oil, sesame oil, soybean oil and more especially groundnut oil.

[0327] The manufacture of injectable preparations is usually carried outunder sterile conditions, as is the filling, for example, into ampoulesor vials, and the sealing of the containers.

[0328] Pharmaceutical compositions for oral administration can beobtained, for example, by combining the active ingredient with one ormore solid carriers, if desired granulating a resulting mixture, andprocessing the mixture or granules, if desired or necessary, by theinclusion of additional excipients, to form tablets or tablet cores.

[0329] Suitable carriers are especially fillers, such as sugars, forexample lactose, saccharose, mannitol or sorbitol, cellulosepreparations, and/or calcium phosphates, for example tricalciumphosphate or calcium hydrogen phosphate, and also binders, such asstarches, for example corn, wheat, rice or potato starch,methylcellulose, hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired,disintegrators, such as the above-mentioned starches, also carboxymethylstarch, crosslinked polyvinylpyrrolidone, alginic acid or a saltthereof, such as sodium alginate. Additional excipients are especiallyflow conditioners and lubricants, for example silicic acid, talc,stearic acid or salts thereof, such as magnesium or calcium stearate,and/or polyethylene glycol, or derivatives thereof.

[0330] Tablet cores can be provided with suitable, optionally enteric,coatings through the use of, inter alia, concentrated sugar solutionswhich may comprise gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethyl cellulose phthalate.Dyes or pigments may be added to the tablets or tablet coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

[0331] Pharmaceutical compositions for oral administration also includehard capsules consisting of gelatin, and also soft, sealed capsulesconsisting of gelatin and a plasticizer, such as glycerol or sorbitol.The hard capsules may contain the active ingredient in the form ofgranules, for example in admixture with fillers, such as corn starch,binders, and/or glidants, such as talc or magnesium stearate, andoptionally stabilizers. In soft capsules, the active ingredient ispreferably dissolved or suspended in suitable liquid excipients, such asfatty oils, paraffin oil or liquid polyethylene glycols or fatty acidesters of ethylene or propylene glycol, to which stabilizers anddetergents, for example of the polyoxyethylene sorbitan fatty acid estertype, may also be added.

[0332] Pharmaceutical compositions suitable for rectal administrationare, for example, suppositories that consist of a combination of theactive ingredient and a suppository base. Suitable suppository basesare, for example, natural or synthetic triglycerides, paraffinhydrocarbons, polyethylene glycols or higher alkanols.

[0333] For parenteral administration, aqueous solutions of an activeingredient in water-soluble form, for example of a water-soluble salt,or aqueous injection suspensions that contain viscosity-increasingsubstances, for example sodium carboxymethylcellulose, sorbitol and/ordextran, and, if desired, stabilizers, are especially suitable. Theactive ingredient, optionally together with excipients, can also be inthe form of a lyophilizate and can be made into a solution beforeparenteral administration by the addition of suitable solvents.

[0334] Solutions such as are used, for example, for parenteraladministration can also be employed as infusion solutions.

[0335] Preferred preservatives are, for example, antioxidants, such asascorbic acid, or microbicides, such as sorbic acid or benzoic acid.

[0336] The invention relates likewise to a process or a method for thetreatment of one of the pathological conditions mentioned hereinabove,especially a disease which responds to an inhibition of theVEGF-receptor tyrosine kinase or an inhibition of angiogenesis,especially a corresponding neoplastic disease or also psoriasis. Thecompounds of formula I or N-oxides thereof can be administered as suchor especially in the form of pharmaceutical compositions,prophylactically or therapeutically, preferably in an amount effectiveagainst the said diseases, to a warm-blooded animal, for example ahuman, requiring such treatment. In the case of an individual having abodyweight of about 70 kg the daily dose administered is fromapproximately 0.1 g to approximately 5 9, preferably from approximately0.5 g to approximately 2 g, of a compound of the present invention.

[0337] The present invention relates especially also to the use of acompound of formula I, or a pharmaceutically acceptable salt thereof,especially a compound of formula I or N-oxides thereof which is said tobe preferred, or a pharmaceutically acceptable salt thereof, as such orin the form of a pharmaceutical formulation with at least onepharmaceutically acceptable carrier for the therapeutic and alsoprophylactic management of one or more of the diseases mentionedhereinabove, especially a neoplastic disease or also psoriasis, moreespecially if the disease responds to an inhibition of angiogenesis oran inhibition of VEGF-receptor tyrosine kinase.

[0338] The present invention relates especially also to the use of acompound of formula I or N-oxides thereof, or a pharmaceuticallyacceptable salt thereof, especially a compound of formula I which issaid to be preferred, or a pharmaceutically acceptable salt thereof, assuch or in the form of a pharmaceutical formulation with at least onepharmaceutically acceptable carrier for the therapeutic and alsoprophylactic management of one or more of the diseases mentionedhereinabove, preferably a disease which responds to an inhibition ofVEGF-receptor tyrosine kinase or an inhibition of angiogenesis,especially a neoplastic disease or also psoriasis, more especially ifthe said disease responds to an inhibition of VEGF-receptor tyrosinekinase or angiogenesis.

[0339] The present invention relates especially also to the use of acompound of formula I or N-oxides thereof, or a pharmaceuticallyacceptable salt thereof, especially a compound of formula I which issaid to be preferred, or a pharmaceutically acceptable salt thereof, forthe preparation of a pharmaceutical formulation for the therapeutic andalso prophylactic management of one or more of the diseases mentionedhereinabove, especially a neoplastic disease or also psoriasis, moreespecially if the disease responds to an inhibition of VEGF-receptortyrosine kinase or angiogenesis.

[0340] The preferred dose quantity, composition, and preparation ofpharmaceutical formulations (medicines) which are to be used in eachcase are described above.

[0341] Starting materials

[0342] New starting materials and/or intermediates, as well as processesfor the preparation thereof, are likewise the subject of this invention.In the preferred embodiment, such starting materials are used andreaction conditions so selected as to enable the preferred compounds tobe obtained.

[0343] Starting materials of the formula II, III, IVa, IVb, V, VI, VIIand VIII are known, are commercially available, or can be synthesized inanalogy to or according to methods that are known in the art.

[0344] For example, an aniline of the formula II can be prepared from anitro compound of the formula IX,

[0345] wherein R₁, R₃ to R₇ and W have the meanings as given underformula I.

[0346] The reduction preferably takes place in the presence of asuitable reducing agent, such as tin(lI) chloride or hydrogen in thepresence of an appropriate catalyst, such as Raney nickel (thenpreferably the hydrogen is used under pressure, e.g. between 2 and 20bar) or PtO₂, in an appropriate solvent, e.g. an alcohol, such asmethanol. The reaction temperature is preferably between 0 and 80° C.,especially 15 to 30° C.

[0347] A nitro compound of the formula IX is accessible by reaction ofan acid of the formula X,

[0348] wherein W is oxygen and R₃ to R₆ are as defined above, or anactivated derivative thereof, is reacted with an amine of the formulaXI,

HNR₁R₇   (XI)

[0349] wherein R₁ and R₇ are as defined under formula I, e.g. in thepresence of a coupling agent, such as dicyclohexylcarbodiimide, at atemperature between 0° C. and 50° C., preferably at room temperature.

[0350] If required, W═O can be changed to W═S with Lawesson's agent, asdescribed above for the analogous conversion of a compound of formula Iwith W =0 into one with W═S.

[0351] It would also be possible to first reduce the nitro compound ofthe formula X to the corresponding aniline compound under reactionconditions analogous to those for the reduction of nitro compounds ofthe formula IX and then react the resulting anilino compound with theamino compound of formula XI under analogous conditions as decribedabove. However, it may then be nesessary to protect the aniline aminogroup.

[0352] An anthranilic acid derivative of the formula VII is accesiblethrough the reductive amination reaction of a compound of formula XII

[0353] wherein R₃, R₄, R₅ and R₆ are as defined for a compound of theformula I and R₁₁ is lower alkyl or aryl, by first reacting the compoundof formula XII with 4-pyridine-carbaldehyde and then with a reducingagent, e.g. sodium cyanotrihydrido-borate, in a one-step procedure in alower alkanol, e.g. methanol, ethanol or propanol, at a temperaturebetween 0° C. and 50° C., e.g. at room temperature.

[0354] The reaction sequence of first obtaining an imine starting fromthe amine of formula XII and then reducing it can also be accomplishedin separate reaction steps. Reagents which can be used to add hydrogento an imine double bond include borane in tetrahydrofuran, LiAlH₄,NaBH₄, sodium in ethanol and hydrogen in the presence of a catalyst.

[0355] All remaining starting materials of are known, capable of beingprepared according to known processes, or commercially obtainable; inparticular, they can be prepared using processes as described in theExamples.

[0356] In the preparation of starting materials, existing functionalgroups which do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described under “protecting goups” or in the Examples.

EXAMPLES

[0357] The following Examples serve to illustrate the invention withoutlimiting the invention in its scope.

[0358] Temperatures are measured in degrees celsius (° C.). Unlessotherwise indicated, the reactions take place at room temperature.

[0359] Preparation of Intermediates:

[0360] 1. Intermediate 1a: 2-Nitro-N-(4-trifluoromethylphenyl)benzamide

[0361] A solution containing 2-nitrobenzoyl chloride (Fluka, Buchs,Switzerland) (1.97 mL, 15 mmol) and 4-dimethylaminopyridine (Fluka,Buchs, Switzerland) (10 mg) in dichloromethane (10 mL) is added to astirred mixture of 4-aminobenzotrifluoride (Fluka, Buchs, Switzerland)(2.66 g, 16.5 mmol) and triethylamine (1.90 g, 18.8 mmol) indichloromethane (100 mL) under an argon atmosphere and the mixture isstirred for 16 hours at 25° C. The stirred mixture is then treated witha saturated aqueous solution of sodium hydrogen carbonate (50 mL) andthen extracted with dichoromethane (2×50 mL). The combined extracts aredried (Na₂SO₄), filtered and the solvent is evaporated off under reducedpressure to yield the crude product which is purified by columnchromatography on silica gel, eluent 10-50% ethyl acetate in hexane, togive the title compound as a colourless crystalline solid.

[0362] Intermediate 1b:2-Nitro-N-[3-fluoro-(4-trifluoromethyl)phenyl]benzamide

[0363] A solution of 4-amino-2-fluorobenzotrifluoride (Fluorochem,Derbyshire, England; 14.4 g, 75 mmol) in ethyl acetate (150 mL) wasadded to a stirred solution of sodium hydroxide (3.30 g, 82.5 mmol) inwater, at room temperature. This stirred solution was then treateddropwise over 30 minutes with a solution of 2-nitrobenzoyl chloride(11.0 mL, 82.5 mmol) in dry ethyl acetate (110 mL). The resultingmixture was then stirred overnight at ambient temperature. The mixtureis then extracted with ethyl acetate (3×100 mL). The combined extractsare sequentially washed with water (2×100 mL), hydrochloric aciid (2×100mL of 2M), water (2×100 mL), saturated aqueous sodium hydrogen carbonatesolution (2×100 mL) and saturated aqueous sodium chloride (1×100 mL),dried (Na₂SO₄), filtered and the solvent is evaporated off under reducedpressure to yield the crude product which is purified byrecrystallisation from ethyl acetate-hexane to give the title compoundas a colourless crystalline solid, m.p. 185-189° C.

[0364] The following compounds are prepared analogously by utilising theappropriate amine (the supplier of which is e.g. Fluka or Aldrich, bothBuchs, Switzerland, or mentioned in parenthesis):

[0365] (1c) 2-Nitro-N-(4-chlorophenyl)benzamide, utilizing4-chloroaniline,

[0366] (1d) 2-Nitro-N-(4-methylphenyl)benzamide, utilizing4-methylaniline,

[0367] (1e) 2-Nitro-N-(3-fluoro-4-methylphenyl)benzamide, utilizing3-fluoro-4-methylaniline (Riedel-de Haen, Seelze, Germany),

[0368] (1f) 2-Nitro-N-[4-chloro-(3-trifluoromethyl)phenyl]benzamide,utilising 4-chloro-3-(trifluoromethyl)benzenamine,

[0369] (1g) 2-Nitro-N-[3-chloro-(5-trifluoromethyl)phenyl]benzamide,utilizing 3-amino-5-chlorobenzotrifluoride, prepared from4-amino-3-chloro-5-nitrobenzotrifluoride (Maybridge Chemical Co. Ltd.)as described in European Patent Application EP 0 516 297),

[0370] (1h) 2-Nitro-N-[4-fluoro-(3-trifluoromethyl)phenyl]benzamide,utilizing 4-fluoro-3-(trifluoromethyl)benzenamine,

[0371] (1i) 2-Nitro-N-[3-fluoro-(5-trifluoromethyl)phenyl]benzamide,utilizing 3-fluoro-5-trifluoromethyl)benzenamine (Fluorochem,Derbyshire, England),

[0372] (1j) 2-Nitro-N-[3,5-(bis-trifluoromethyl)phenyl]benzamide,utilizing 3,5-(bistrifluoromethyl)benzenamine,

[0373] (1k) 2-Nitro-N-[3,4-(bis-trifluoromethyl)phenyllbenzamide,utilizing 3,4-(bistrifluoromethyl)benzenamine,

[0374] (1k) 2-Nitro-N-[3-methoxy-(5-trifluoromethyl)phenyl]benzamide,utilizing 3-methoxy-5-(trifluoromethyl)benzenamine,

[0375] (1m) 2-Nitro-N-[3-(trifluoromethyl)phenyl]benzamide, utilizing3-(trifluoromethyl)benzenamine,

[0376] (1n) 2-Nitro-N-[3-(1,1-dimethyl)ethyl)phenyl]benzamide, utilizing3-tert-butylaniline,

[0377] (1o) 2-Nitro-N-(3-cyanophenyl)benzamide, utilizing3-cyanobenzenamine,

[0378] (1p) 2-Nitro-N-(3-methylthiophenyl)benzamide, utilizing3-methylthiobenzenamine,

[0379] (1q) 2-Nitro-N-[3-[(1-oxoethyl)amino]phenyl]benzamide, utilizing3-methylthiobenzenamine (Pfaltz and Bauer Inc, Connecticut, USA),

[0380] (1r) 2-Nitro-N-[3-[(aminocarbonyl)amino]phenyl]benzamide,utilising 3-aminophenylurea (Bayer Organica, Leverkusen, Germany),

[0381] (1s) 2-Nitro-N-[3-(dimethylamino)phenyl]benzamide, utilisingN,N-dimethyl-1,3-benzenediamine, dihydrochloride (Lancaster Synthesis,Lancashire, England),

[0382] (1t) 5-Methoxy-2-nitro-N-[3-(trifluoromethyl)phenyllbenzamide,utilising 5-methoxy-2-nitrobenzoyl chloride (which may be prepared asdescribed by Sami Khan and LaMontagne, J. Med. Chem. 1979;22:1005-1008,from 5-methoxy-2-nitrobenzoic acid) and 3-(trifluoromethyl)benzenamine,

[0383] (1u) 3-Methyl-2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide,utilising 3-methyl-2-nitrobenzoyl chloride (which may be prepared asdescribed by Edge et al, J. Chem. Soc. Perkin Trans. 1 1982; 1701-1714,from 3-methyl-2-nitrobenzoic acid) and 3-(trifluoromethyl)benzenamine,

[0384] (1v) 4,5-Difluoro-2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide,utilising 4,5-difluoro-2-nitrobenzoyl chloride prepared from4,5-difluoro-2-nitrobenzoic acid as described in German PatentApplication DE 3717904.

[0385] (1w) 2-Nitro-N-methyl-N-[3-(trifluoromethyl)phenyl]benzamide,utilizing N-methyl-3-(trifluoromethyl)benzenamine prepared as describedby Berbalk et al, Monatshefte Chemie 1976;107: 401-404, from3-(trifluoromethyl)benzenamine,

[0386] (1x) 2-Bromo-N-[3-(trifluoromethyl)phenyl]benzamide, utilising2-bromobenzoyl chloride in lieu of 2-nitrobenzoyl chloride and3-(trifluoromethyl)benzenamine.

[0387] Intermediate 1v: 2-Nitro-N-[(3-methylsulphonyl)phenyl]benzamide

[0388] 3-Chloroperoxybenzoic acid (71.8 g of 55%, 229 mmol ) is added toa stirred mixture of 2-Nitro-N-(3-methylthiophenyl)benzamide(intermediate 1p; 22.0 g, 76.3 mmol) in dichloromethane (1 L) at 0° C.The resulting mixture is then stirred at 35° C. for 70 hours. Themixture is then washed sequentially with aqueous sodium hydroxide (2×100mL) and aqueous sodium thiosulphate (2×50 mL of 10%). The organic phaseis dried (Na₂SO₄), filtered and the solvent is evaporated off underreduced pressure to yield the crude product which is purified by columnchromatography on silica gel, eluent 50% ethyl acetate in hexane andrecrystallised from diisopropyl ether to give the title compound as acolourless crystalline solid, m.p. 172-173° C.

[0389] 2. Intermediate 2a: 2-Amino-N-(4-trifluoromethylphenyl)benzamide

[0390] A solution of intermediate 1 a (1.92 g, 6.19 mmol) in methanol(200 mL) is hydrogenated at 5 bar over Raney nickel (400 mg) at 21° C.The calculated amount of hydrogen is taken up in 1 hour. The mixture isthen filtered and the solvent is evaporated off under reduced pressureto yield the crude product which is purified by recrystallisation fromdichloromethane-hexane to give the title compound as a colourlesscrystalline solid, m.p. 160-161° C.

[0391] The following compounds are prepared analogously by utilising theappropriate amine:

[0392] (2b) 2-Amino-N-[3-fluoro-4-(trifluoromethyl)phenyl]benzamide,m.p. 135-137° C., utilising intermediate 1b. (2c)2-Amino-N-(4-chlorophenyl)benzamide, m.p. of the hydrochloride salt156-173° C., utilising intermediate 1c.

[0393] (2d) 2-Amino-N-(4-methylphenyl)benzamide, utilising intermediate1d.

[0394] (2e) 2-Amino-N-(3-fluoro-4-methylphenyl)benzamide, m.p. 149-151°C., utilising intermediate 1e.

[0395] (2f) 2-Amino-N-[4-chloro-3-(trifluoromethyl)phenyl]benzamide,m.p. 148-150° C., utilising intermediate 1f.

[0396] (2g) 2-Amino N-[3-chloro-5-(trifluoromethyl)phenyl]benzamide,m.p. 174-175° C., utilising intermediate 1g.

[0397] (2h) 2-Amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]benzamide,m.p. 159-162° C., utilising intermediate 1h.

[0398] (2i) 2-Amino-N-[3-fluoro-5-(trifluoromethyl)phenyl]benzamide,m.p. 142-144° C., utilising intermediate 1i.

[0399] (2j) 2-Amino-N-[3,5-(bis-trifluoromethyl)phenyl]benzamide, m.p.192-193° C., utilising intermediate 1j.

[0400] (2k) 2-Amino-N-[3,4-(bis-trifluoromethyl)phenyl]benzamide,utilising intermediate 1k.(21)2-Amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide, m.p.125-126° C., utilising intermediate 1l.

[0401] (2m) 2-Amino-N-[3-(trifluoromethyl)phenyl]benzamide, m.p.131-133° C., utilising intermediate 1m.

[0402] (2n) 2-Amino-N-[3-(1,1-dimethyl)ethyl)phenyl]benzamide, m.p.84-86° C., utilising intermediate 1n.

[0403] (2o) 2-Amino-N-(3-cyanophenyl)benzamide, m.p. 161-163° C.,utilising intermediate 1o.

[0404] (2p) 2-Amino-N-(3-methylthiophenyl)benzamide, m.p. 88-90° C.,utilising intermediate 1p.

[0405] (2q) 2-Amino-N-[3-[(1-oxoethyl)amino]phenyl]benzamide, m.p.132-134° C., utilising intermediate 1q.

[0406] (2r) 2-Amino- N-[3-[(aminocarbonyl)amino]phenyl]benzamide, m.p.187-189° C., utilising intermediate 1r.

[0407] (2s) 2-Amino-N-[3-(dimethylamino)phenyl]benzamide, m.p. 109-110°C., utilising intermediate 1s.

[0408] (2t) 2-Amino-5-methoxy-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 98-99° C., utilising intermediate 1t.

[0409] (2u) 2-Amino-3-methyl-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 103-108° C., utilising intermediate 1u.

[0410] (2v) 2-Amino-4,5difluoro-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 198-200° C., utilising intermediate 1v.

[0411] (2w) 2-Amino-N′-methyl-N′-[3-(trifluoromethyl)phenyl]benzamide,m.p. 61-64° C., utilising intermediate 1w.

[0412] Intermediate 2x: 2-Amino-N-[(3-methylsulphonyl)phenyl]benzamide

[0413] A solution of intermediate 1y (22.0 g, 68.7 mmol) in methanol(1500 mL) is hydrogenated at 7 bar over 10% palladium on carbon (1.0 g)at 22° C. The calculated amount of hydrogen is taken up in 1 hour. Themixture is then filtered and the solvent is evaporated off under reducedpressure to yield the crude product which is purified by columnchromatography on silica gel, eluent ethyl acetate and recrystallisationfrom diisopropyl ether-hexane to give the title compound as a colourlesscrystalline solid, m.p. 190-193° C.

[0414] Intermediate 2v: 2-Amino- [(3-methylsulphinyl)phenyl]benzamide

[0415] A solution of intermediate 2p (2.58 g, 10 mmol) in ethanol (100mL) is added dropwise over 30 min to a stirred solution of sodiummetaperiodate (2.25 g, 10.5 mmol) mixed solvent (100 ml of ethanol and100 ml of H₂O) at 0° C. The mixture is stirred at 5° C. for 17 hours andthen diluted with water (600 mL) and extracted with dichloromethane(3×150 mL). The combined extracts are dried (Na₂SO₄), filtered and thesolvent is evaporated off under reduced pressure to yield the crudeproduct which is purified by column chromatography on silica gel, eluentethyl acetate and recrystallised from isopropanol-diisopropylether togive the title compound as a colourless crystalline solid, m.p. 117-121°C.

[0416] Intermediate 2z: 2-Amino N[4-(1,1-dimethyl)ethyl)phenyl]benzamide

[0417] A solution of 4-tert-butylaniline (9.00 g, 60.3 mmol) indimethylformamide (20 mL) is added to a stirred solution of isatoicanhydride (9.75 g, 60 mmol) in dimethylformamide (80 mL) at 100° C. Themixture is stirred at 100° C. for 4 hours. The solvent is thenevaporated off under reduced pressure to give a residue which isdissolved in ethyl acetate (300 mL) and washed with saturated aqueousammonium chloride solution. The solution is dried (Na₂SO₄), filtered andthe solvent is evaporated off under reduced pressure to yield theproduct which is purified by column chromatography on silica gel, eluent10% ethyl acetate in hexane and recrystallised from t butylmethylether-cyclohexane to give the title compound as a colourless crystallinesolid, m.p. 132-134° C.

[0418] The following compounds are prepared analogously by utilising theappropriate amine:

[0419] (2aa) 2-Amino-N-(3-chlorophenyl)benzamide, m.p. 136-137C,utilizing 3-chloroaniline;

[0420] (2ab) 2-Amino-1(3-bromophenyl)benzamide, m.p. 150-153° C.,utilizing 3-bromoaniline;

[0421] (2ac) 2-Amino-N-(3-methylphenyl)benzamide, m.p. 115-117° C.,utilizing 3-methylaniline;

[0422] (2ad) 2-Amino-N-(3-benzoylphenyl)benzamide, as a yellow oil,utilizing (3-aminophenyl)phenylmethanone;

[0423] (2ae) 2-Amino-N-[(3-aminocarbonyl)phenyl]benzamide, utilizing3-aminobenzamide.

[0424] Intermediate 2af: 2-Amino-N-(4-methylphenyl)-6-methylbenzamide

[0425] (i) 2-{((1,1-Dimethylethoxy)carbonyl]amino)-6-methylbenzoic acid

[0426] A stirred solution of 2-amino-6-methylbenzoic acid (9.90 g, 65.5mmol), triethylamine (12.4 mL, 9.00 g, 89.10 mmol) in drydimethylformamide (300 mL) under an argon atmosphere, is treated withdi-t-butyl dicarbonate (19.44 g, 89.1 mmol) and stirred at 18° C. for 18hours. The solvent is evaporated off under reduced pressure to give aresidue which is treated with aqueous citric acid solution (100 mL of10%) and extracted with dichloromethane (2×100 mL). The combinedextracts are dried (Na₂SO₄), filtered and the solvent is evaporated offunder reduced pressure to yield the product which is purified by columnchromatography on silica gel, eluent 5% methanol in dichloromethane andrecrystallised from t-butylmethyl ether-hexane to give the titlecompound as a colourless crystalline solid.

[0427] (ii)N-(4-Methylphenyl)-2-{[(1,1-dimethylethoxy)carbonyl]amino]-6-methylbenzamide

[0428] Firstly N-methylmorpholine (6.15 mL, 5.64 g, 55.8 mmol) and thenO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(10.15 g, 26.8 mmol) are added to a stirred mixture of 2-{[(1,1-dimethylethoxy)carbonyl]amino)-6-methylbenzoic acid (5.60 g, 22.3mmol) and p-toluidine 4.78 g, 44.6 mmol) in dry dimethylformamide (110mL) under an argon atmosphere, and stirred at 18° C. for 16 hours. Thesolvent is evaporated off under reduced pressure to give a residue whichis treated with aqueous sodium hydrogen carbonate solution (200 mL of10%) and extracted with dichloromethane (3×100 mL). The combinedextracts are washed with aqueous citric acid solution (100 mL of 10%),dried (Na₂SO₄), filtered and the solvent is evaporated off under reducedpressure to yield the crude product which is purified by columnchromatography on silica gel, eluent 20% ethyl acetate in hexane, andrecrystallised from tert-butylmethyl ether-hexane to give the titlecompound as a colourless crystalline solid, m.p. 250° C.

[0429] (iii) 2-Amino-N-(4-methylphenyl)-6-methylbenzamide, hydrochloride

[0430] A stirred solution ofN-(4-methylphenyl)-2-{[(1,1-dimethylethoxy)carbonyl]amino)-6-methylbenzamide(1.67 g, 4.90 mmol) in methanol (4 mL) under an argon atmosphere, istreated with a saturated solution of hydrogen chloride in dioxane (30mL) and stirred at 18° C. for 210 minutes. The solvent is evaporated offunder reduced pressure to give the crude product which is purified byrecrystallisation from methanol - di-isopropyl ether to give the titlecompound as a colourless crystalline solid, m.p. 217-220° C.

EXAMPLES Example 1:

[0431]2-[(4-Pyridyl)methyl]amino-N-[4-(trifluoromethyl)phenyl]benzamide

[0432] Sodium cyanoborohydride (0.80 g of 90%, 11.5 mmol) is added inportions over 30 minutes to a stirred mixture of acetic acid (0.15 mL),4-pyridinecarboxaldehyde (1.00 g, 3.57 mmol) and intermediate 2a (1.00g, 3.57 mmol) in methanol (15 mL) at 25° C. under an argon atmosphere.The mixture is stirred for 16 hours, diluted with dichloromethane (100mL) and treated with a saturated aqueous solution of sodium hydrogencarbonate (50 mL). The mixture is stirred for an additional 5 min andthen extracted with dichoromethane (3×50 mL). The combined extracts aredried (Na₂SO₄), filtered and the solvent is evaporated off under reducedpressure to yield the crude product that is purified by columnchromatography on silica gel, eluent 33% ethyl acetate in hexane, andrecrystallised from 2-propanol - hexane to give the title compound as acolourless crystalline solid, m.p. 171-175° C. and having the followingphysical characteristics: ¹H-NMR (DMSO-d₆) d 4.49 (d, J=6.1 Hz, 2H),6.56 (d, J=8.4 Hz, 1H), 6.66 (t, J=8.5 Hz, 1H), 7.26 (t, J=8.4 Hz, 1H),7.33 (d, J=5.9 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.72 (m, 1H), 7.90 (t,J=6.1 Hz, 1H), 7.96 (d, J=8.5 Hz, 2H), 8.49 (d, J=5.9 Hz, 2H) and 10.46(s, 1H).

[0433] The following compounds are prepared analogously by utilising theappropriate amine:

Example 2:

[0434]2-[(4-Pyridyl)methyl]amino-N-[3-fluoro-(4-trifluoromethyl)phenyl]benzamide,m.p. 162-164° C., utilising intermediate 2b.

Example 3:

[0435]2-[(4-Pyridyl)methyl]amino-N-phenylbenzamide, m.p. 160-161° C.,utilising 2-aminobenzanilide.

Example 4:

[0436]2-[(4-Pyridyl)methyl]amino-N-(4chlorophenyl)benzamide, m.p.134-139° C., utilising intermediate 2c.

Example 5:

[0437]2-1(4-Pyridyl)methyl]amino-1(4-methylphenyl)benzamide, utilisingintermediate 2d.

Example 6:

[0438]2-[(4-Pyridyl)methyl]amino-N-(3-fluoro-4-methylphenyl)benzamide isprepared utilising intermediate 2e. Following purification bychromatography (silica gel, eluent 33% ethyl acetate in hexane), thebase is dissolved in ethyl acetate and treated with a solution ofhydrogen chloride in dichloromethane. The precipitated product isfiltered off and recrystallized from dichloromethane-hexane to affordthe dihydrochloride salt, m.p. 116-124° C.

Example 7:

[0439]2-[(4-Pyridyl)methyl]amino-N-[4-chloro-3-(trifluoromethyl)phenyl]benzamide,m.p. 162-172° C., utilising intermediate 2f.

Example 8:

[0440]2-[(4-Pyridyl)methyl]amino-N-[3-chloro-5-(trifluoromethyl)phenyl]benzamide,m.p. 190-194° C., utilising intermediate 2g.

Example 9:

[0441]2-1(4-Pyridyl)methyl]amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]benzamide,m.p. 183-185° C., utilising intermediate 2h.

Example 10:

[0442]2-[(4-Pyridyl)methyl]amino-N-13-fluoro-5-(trifluoromethyl)phenyl]benzamide,m.p. 196-197° C., utilising intermediate 2i.

Example 11:

[0443]2-[(4-Pyridyl)methyl]amino-N-[3,5-(bistrifluoromethyl)phenylbenzamide,m.p. 180-185° C., utilising intermediate 2j.

Example 12:

[0444]2-(4-Pyridyl)methyl]amino-N-[3,4-(bistrifluoromethyl)phenylbenzamide,utilising intermediate 2k.

Example 13:

[0445]2-[(4-Pyridyl)methyl]amino-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide,m.p. 134-136° C., utilising intermediate 2l.

Example 14:

[0446]2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 157-159° C., utilising intermediate 2m.

Example 15:

[0447]2-[(4-Pyridyl)methyl]amino-[3-(1,1-dimethylethyl)phenyl]benzamide, m.p. 144-147° C., utilisingintermediate 2n.

Example 16:

[0448]2-[(4-Pyridyl)methyl]amino-N-(3 cyanophenyl)benzamide, m.p.157-160° C., utilising intermediate 2o.

Example 17:

[0449]2[(4-Pyridyl)methyl]amino-N-(3-methylthio)phenyl]benzamide, m.p.138-142° C., utilising intermediate 2p.

Example 18:

[0450]2-[(4-Pyridyl)methyl]amino-N-(3-acetylaminophenyl)benzamide, m.p.157-158° C., utilising intermediate 2q.

Example 19:

[0451]2-[(4-Pyridyl)methyl]amino-N-3-[(aminocarbonyl)amino]phenyl]benzamide,m.p. 200-202° C., utilising intermediate 2r.

Example 20:

[0452]2-[(4-Pyridyl)methyl]amino-N-[3-(dimethylamino)phenyl]benzamide,m.p. 152-154° C., utilising intermediate 2s.

Example 21:

[0453]5-Methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 175-178° C., utilising intermediate 2t.

Example 22:

[0454]3-Methyl-2-[(4-pyridyl)methyl]amino-N-[3(trifluoromethyl)phenyl]benzamideis prepared utilising intermediate 2u.

[0455] Following purification by column chromatography (silica gel,eluent: 33% hexane in ethyl acetate) the base is dissolved in ethylacetate and treated with a solution of hydrogen chloride indichloromethane. The precipitated product is filtered off andrecrystallized from ethyl acetate to afford the dihydrochloride salt,m.p. 94-98° C.

Example 23:

[0456]4,5-Difluoro-2-[(4-pyridyl)methylamino-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 175-178° C., utilising intermediate 2v.

Example 24:

[0457]2-[(4-Pyridyl)methyl]amino-N-methyl-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 127-128° C., utilising intermediate 2w.

Example 25:

[0458]2-[(4-Pyridyl)methyl]amino-N-[(3-methylsulphonyl)phenyl]benzamide,m.p. 178-184° C., utilising intermediate 2x.

Example 26:

[0459]2-[(4-Pyridyl)methyl]amino-N-[(3-methylsulphinylphenyl]benzamide,m.p. 175-178° C., utilising intermediate 2y.

Example 27:

[0460]2-[4-Pyridyl)methyl]amino-N-[4-(1,1-dimethylethyl)phenyl]benzamide,m.p. 168-170° C., utilising intermediate 2z.

Example 28:

[0461]2-[(4-Pyridyl)methyl)amino-i(3-chlorophenyl)benzamide, m.p.131-133° C., utilising intermediate 2aa.

Example 29:

[0462]2-[(4-Pyridyl)methyl]amino-4(3-bromophenyl)benzamide, m.p.156-159° C., utilising intermediate 2ab.

Example 30:

[0463]2-[(4-Pyridyl)methyl]amino-N-(3-methylphenyl)benzamide, m.p.139-140° C., utilising intermediate 2ac.

Example 31:

[0464]2-[(4-Pyridyl)methyl]amino-i(3-benzoylphenyl)benzamide, m.p.168-169° C., utilising intermediate 2ad.

Example 32:

[0465]2-[(4-Pyridyl)methyl]amino-N-[3-(aminocarbonyl)phenyl]benzamide,m.p. 195-203° C., utilising intermediate 2ae.

Example 33:

[0466]2-[(4-Pyridyl)methyl]amino-N-(4-methylphenyl)-6-methylbenzamide,m.p. 162-163° C., utilising intermediate 2af.

[0467] The following compounds are prepared by a method analogous tothat described in Example 14, by utilising the appropriate aldehyde:

Example 34:

[0468]2-[(3-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 140-142° C., utilising 3-pyridinecarboxaldehyde.

Example 35:

[0469]2-[(4-Quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 191-193° C., utilising 4quinolinecarboxaldehyde.

Example 36:

[0470]2-[(5-Quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 176-178° C., utilising 5-quinolinecarboxaldehyde prepared asdescribed by Wommack et al, J.Het.Chem. 1969;6:243-245, from5-aminoquinoline.

Example 37:

[0471]2-1(4-(2-Methyl)pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 146-147° C., utilising 2-methyl-4-pyridinecarboxaldehyde preparedas described by Boehm et al, J. Med. Chem. 1996;39:3929-3937 from2-methyl-4-cyanopyridine, which was in turn prepared by the method ofAshimori et al, Chem. Pharm. Bull. 1990;38:2446-2458 from2-methylpyridine-1-oxide.

Example 38:

[0472]2-[(4-(1,2-Dihydro-2-oxo)pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide, m.p. 183-185° C., utilising1,2-dihydro-2-oxo-4-pyridinecarboxaldehyde prepared as described by Ren,Sakai and Nakanishi, J. Amer. Chem. Soc. 1997;119:3619-3620 from2-hydroxy-4-methylpyridine.

Example 39:

[0473]2-[(4-Quinolinyl)methyl]amino-N-(4-chlorophenyl)benzamide, m.p.178-209° C., is prepared by a method analogous to that described inExample 4, by utilising 4-quinoline-carboxaldehyde.

Example 40:

[0474]2-[(2-Imidazolyl)methyl]amino-N-(4chlorophenyl)benzamide, m.p.181-184° C., is prepared by a method analogous to that described inExample 4, by utilising 1H-imidazole-2-carboxaldehyde.

Example 41:

[0475]2-[2-(4-Pyridyl)ethyl]amino-)N-[3-(trifluoromethyl)phenyl]benzamide4-Pyridineethanamine (Maybridge Chemical Co, Cornwall, England; 0.31 9,2.5 mmol) is added to a stirred mixture of2-bromo-N-[3-(trifluoromethyl)phenyl]benzamide (intermediate 1x; 1.72 g,5 mmol), powdered potassium carbonate (0.35 9, 2.5 mmol) andcopper(1)iodide (Fluka, Buchs, Switzerland; 0.48 g, 2.5 mmol) indimethylformamide (10 mL). The resulting mixture is then purged withargon and subsequently heated at 160° C. under an argon atmosphere for15 hours. The mixture is cooled, treated with water (100 mL) andextracted with ethyl acetate (3×80 mL). The combined extracts arewashesdwith an aqueous solution of ammonia (2×10%), dried (Na₂SO₄),filtered and the solvent is evaporated off under reduced pressure toyield the crude product which is purified by column chromatography onsilica gel, eluent 50% ethyl acetate in hexane and recrystallised fromethyl acetate-hexane to give the title compound as a colourlesscrystalline solid, m.p. 151-152° C.

[0476] The following compounds are prepared by a method analogous tothat described in Example 41, by utilising the appropriate amine:

Example 42:

[0477]2-[2-(3-Pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,m.p. 102-103° C., utilising 3-pyridineethanamine (Maybridge Chemical Co,Cornwall, England).

Example 43:

[0478]2-[1-Methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,utilising 1-(3-pyridyl)-2-propylamine prepared as described by in J.Amer. Chem. Soc. 1997;119:3619-3620.

Example 44:

[0479]2-[(1-Oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide3-Chloroperoxybenzoic acid (2.06 g of 70%, 8.4 mmol) is added to astirred mixture of2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide(Example 14; 1.86 g, 5 mmol) in dichloromethane (50 mL) at 0C. Theresulting mixture is then stirred at room temperature for 15 hours. Themixture is diluted with dichloromethane (100 mL) and washed sequentiallywith aqueous sodium hydroxide (2×100 mL) and aqueous sodium thiosulphate(2×50 mL of 10%). The organic phase is dried (Na₂SO₄), filtered and thesolvent is evaporated off under reduced pressure to yield the crudeproduct which is purified by column chromatography on silica gel, eluent20% ethanol in ethyl acetate, and recrystallised from ethylacetate-hexane to give the title compound as a colourless crystallinesolid, m.p. 181-184° C.

Example 45:

[0480]2-[(4-Pyridyl)methyl]methylamino-N-[3-(trifluoromethyl)phenyl]benzamideSodium cyanoborohydride (0.55 g, 14.1 mmol) is added to a stirredmixture of paraformaldehyde (0.82 g, 27.3 mmol) and2-[(4-pyridyl)methyl]amino-M-[3-(trifluoromethyl)phenyl]-benzamide(Example 14; 1.03 g, 2.78 mmol) in tetrahydrofuran (30 mL) at 20° C.under an argon atmosphere. The resulting mixture is then treateddropwise with trifluoroacetic acid (15 mL) and stirred at roomtemperature for 20 hours. The mixture diluted with ice-cold aqueoussodium hydroxide (100 mL of 5M) and extracted with dichloromethane(3×100 mL). The organic phase is dried (Na₂SO₄), filtered and thesolvent is evaporated off under reduced pressure to yield the crudeproduct which is purified by column chromatography on silica gel, eluentethyl acetate, to give the title compound as a colourless crystallinesolid.

Example 46:

[0481]2-[(4-Pyridyl)methyl]methylamino-N-(4-chloronaphthyl)benzamide0.75 ml Trimethylaluminium (2M in toluene) is added to a suspension of266 mg 4-chloro-1-naphthylamine in 1 mL toluene. After 10 minutes a coldsolution of 242 mg methyl N-(4-pyridylmethyl)-anthranilate in 2 mLtoluene is added. The mixture is stirred for 1 hour at room temperatureand for 1 hour under reflux. After cooling to room temperature saturatedNaHCO₃ solution is added and the mixture extracted with ethyl acetate.The extract is washed with water and saturated sodium chloride solutionand concentrated. The residue is crystallized with ethyl acetate to givethe title compound as a solid with m.p. 137° C.

[0482] Stage 46.1: N-(4-pyridylmethyl)-anthranilate

[0483] 3 mL Acetic acid and 8.6 g 4-pyridinecarbaldehyde are added to asolution of 7.5 g methyl anthranilate in 300 mL methanol. The mixture isstirred for 12 hours under nitrogen atmosphere at room temperature. 5.7g Sodium cyanotrihydridoborate (85%) is added and the mixture is stirredfor 3 hours at room temperature. Additional 1.14 g sodiumcyanotrihydridoborate (85%) is added and the mixture is stirred for 12hours at room temperature. The solvent is evaporated and the residuedissolved in ethyl acetate and washed with saturated NaHCO₃ solution andsaturated sodium chloride solution. The organic extract is concentratedand purified with hexane/ethyl acetate (1:1) on silica gel to yieldmethyl N-(4-pyridylmethyl)-anthranilate with m.p. 86° C.

Examples 47-72

[0484] The compounds of Examples 47-72 were prepared in an analogousmanner by reductive amination followed by amidation with an amine andtrimethylaluminium as described in Example 46. The used anthranilicesters are commercially available or are described below.

[0485] Synthesis of the starting material for Example 47:

[0486] 2-Methyl-nitrobenzoic acid is reacted withtrimethylsilydiazomethane to yield methyl 2-methyl-6-nitrobenzoate withm.p. 44-45° (Chem. Pharm. Bull., Vol. 29, 1475 (1981)). Methyl2-methyl-6-nitrobenzoate is hydrogenated in methanol in the presence ofpalladium, 10% on carbon powder, at room temperature and atmosphericpressure to give methyl 2-methyl-6-aminobenzoate.

Synthesis of the starting material for Example 48

[0487] 2-Amino-6-chlorobenzoic acid is reacted withtrimethylsilyldiazomethane to yield methyl 2-amino-6-chlorobenzoate (Chem. Pharm. Bull. Vol. 29, 1475 (1981)).

Synthesis of the starting material for Example 49

[0488] 3,4-Methylenedioxy-6-nitrobenzaldehyde is converted to methyl3,4-methylenedioxy-6-nitrobenzoate in methanol in the presence of sodiumcyanide and manganese dioxide (Synthetic Commun., 27(7), 1281-1283(1997)). Methyl 3,4-methylenedioxy-6-nitrobenzoate is hydrogenated inethanol in the presence of palladium, 10% on carbon powder, at roomtemperature and atmospheric pressure to give methyl3,4-methylenedioxy-6-aminobenzoate.

Synthesis of the starting material for Example 50

[0489] 0.41 g Sodium nitrite in water is added to 1 g4,5-dimethyl-2-nitroaniline in 3 mL conc. HCl and stirred for 1 hour at+4° C. This solution is added to a mixture of 0.67 g copper (I) cyanide,0.98 g sodium cyanide, 0.32 g sodium carbonate, 25 mL of water and 3 mLtoluene. The mixture is stirred for 12 hours at room temperature andworked up to give 0.45 g 4,5-dimethyl-2-nitrobenzonitrile.4,5-Dimethyl-2-nitrobenzonitrile is reduced with iron powder in aceticacid to yield 4,5-dimethyl-2-aminobenzonitrile.4,5-Dimethyl-2-aminobenzonitrile is heated at reflux for 12 hours inconc. HCl to give 4,5-dimethyl-2-aminobenzoic acid.4,5-Dimethyl-2-aminobenzoic acid is reacted withtrimethylsilyldiazomethane to yield methyl 4,5-dimethyl-2-aminobenzoate(Chem. Pharm. Bull. Vol. 29, 1475 (1981)). TABLE 1 Examples 47-72 Thefollowing compounds are compounds of formula I wherein W is O, X is NH,Y is CH₂, R₂ is 4-pyridyl; R₆ and R₇ are H. Ex. R₁ R₃ R₄ R₅ mp. 474-chlorophenyl methyl H H 190 48 4-chlorophenyl chloro H H 183-185 494-chlorophenyl H —O—CH₂—O— 50 4-chlorophenyl H methyl methyl 514-n-propylphenyl H chloro H 52 4-n-propylphenyl H H H 537-hydroxynaphthyl H H H 54 8-hydroxy-2- H H H 235 naphthyl 554-chlorophenyl H H chloro 186 56 4-chlorophenyl H methyl H 127 575,6,7,8-tetrahydro- H H H 116 naphthyl 58 4-biphenyl H H H 135-136 594-chlorophenyl H chloro H 206-207 60 naphthyl H H H 61 2-napthyl H H H159-160 62 4-methoxyphenyl H H H 63 3-trifluoromethoxy- H H H phenyl 644-methoxy-2- H H H 152-154 naphthyl 65 3-bromo-2- H H H 130-132 naphthyl66 4-(isopropoxy- H H H H 70 carbonyl)-phenyl 67 4-trifluoromethoxy- H HH phenyl 68 4-(isopropyl- H H H 79 carbamoyl)-phenyl 69 3-chloro-4- H HH 143 methylphenyl 70 2-methylphenyl H H H 143 71 3-(methoxy- H H Hcarbonylmethyl)- phenyl 72 4-phenoxyphenyl H H H

Example 73:

[0490] Test for activity against Flt-1 VEGF-receptor tyrosine kinase

[0491] The test is conducted using Flt-1 VEGF-receptor tyrosine kinase,as described hereinabove. The IC₅₀ values determined are given below,insofar as they have been accurately recorded: TABLE 2 Test for activityagainst Flt-1 VEGF-receptor tyrosine kinase Title compound from ExampleIC₅₀(μM) 4 0.18 5 0.26 7 0.56

Example 74: Soft capsules

[0492] 5000 soft gelatin capsules, each comprising as active ingredient0.05 g of one of the compounds of formula I mentioned in the precedingExamples, are prepared as follows: Composition Active ingredient 250 gLauroglycol 2 liters

[0493] Preparation process: The pulverized active ingredient issuspended in Lauroglykol® (propylene glycol laurate, Gattefossé S. A.,Saint Priest, France) and ground in a wet pulverizer to produce aparticle size of about 1 to 3 μm. 0.419 g portions of the mixture arethen introduced into soft gelatin capsules using a capsule-fillingmachine.

What is claimed is:
 1. Use of a compound of formula I,

wherein W is O or S; X is NR₈; Y is CR₉R₁₀-(CH₂)_(n) wherein R₉ and R₁₀are independently of each other hydrogen or lower alkyl, and n is aninteger of from and including 0 to and including 3; or Y is SO₂; R₁ isaryl; R₂ is a mono- or bicyclic heteroaryl group comprising one or morering nitrogen atoms with the exception that R₂ cannot represent2-phthalimidyl, and in case of Y═SO₂ cannot represent2,1,3-benzothiadiazol-4-yl; any of R₃, R₄, R₅ and R₆, independently ofthe other, is H or a substituent other than hydrogen; and R₇ and R₈,independently of each other, are H or lower alkyl; or a N-oxide or apharmaceutically acceptable salt thereof for the preparation of apharmaceutical product for the treatment of a neoplastic disease whichresponds to an inhibition of the VEGF receptor tyrosine kinase activity.2. Use of a compound of formula I, wherein the radicals and symbols havethe meanings as defined in claim 1, or a N-oxide or a pharmaceuticallyacceptable salt thereof for the preparation of a pharmaceutical productfor the treatment of retinopathy or age-related macula degeneration. 3.A method for the treatment of a neoplastic disease which responds to aninhibition of the VEGF-receptor tyrosine kinase activity, whichcomprises administering a compound of formula I or a N-oxide or apharmaceutically acceptable salt thereof, wherein the radicals andsymbols have the meanings as defined in claim 1, in a quantity effectiveagainst the said disease, to a warm-blooded animal requiring suchtreatment.
 4. A method for the treatment of retinopathy or age-relatedmacular degeneration, which comprises administering a compound offormula I or a N-oxide or a pharmaceutically acceptable salt thereof,wherein the radicals and symbols have the meanings as defined in claim1, in a quantity effective against said diseases, to a warm-bloodedanimal requiring such treatment.
 5. A compound of formula I, wherein Wis O or S; X is NR₈; Y is CR₉R₁₀-(CH₂)_(n) wherein R₉ and R₁₀ areindependently of each other hydrogen or lower alkyl, and n is an integerof from and including 0 to and including 3; or Y is SO₂; R₁ is aryl; R₂is a mono- or bicyclic heteroaryl group comprising one or more ringnitrogen atoms with the exception that R₂ cannot represent2-phthalimidyl, and in case of Y═SO₂ cannot represent2,1,3-benzothiadiazol-4-yl; any of R₃, R₄, R₅ and R₆, independently ofthe other, is H or a substituent other than hydrogen; and R₇ and R₈,independently of each other, are H or lower alkyl; with the exception ofthe compound of formula I wherein W is 0, X is NR₈, Y is CH₂, R₁ is4-chlorophenyl, R₂ is 2-pyridyl, R₃, R₄, R₆, R₇ and R₈ are each H and R₆is chloro; or a N-oxide or a pharmaceutically acceptable salt thereof.6. A compound of formula I according to claim 5, wherein W is O or S; Xis NR₈; Y is CHR₉-(CH₂)_(n) wherein R₉ is hydrogen or lower alkyl, and nis an integer of from and including 0 to and including 3; or Y is SO₂;R₁ is aryl; R₂ is a mono- or bicyclic heteroaryl group comprising one ormore ring nitrogen atoms with the exception that R₂ cannot represent2-phthalimidyl, and in case of Y═SO₂ cannot represent2,1,3-benzothiadiazol-4-yl; any of R₃, R₄, R₅ and R₆, independently ofthe other, is H or a substituent other than hydrogen; and R₇ and R₈,independently of each other, are H or lower alkyl; with the exception ofthe compound of formula I wherein W is O, X is NR₈, Y is CH₂, R₁ is4-chlorophenyl, R₂ is 2-pyridyl, R₃, R₄, R₅, R₇ and R₈ are each H and R₆is chloro; or a salt thereof.
 7. A compound of formula I according toclaim 5, wherein W is O or S; X is NR₈; Y is CHR₉-(CH₂)_(n) wherein R₉is H or lower alkyl, and n is 0 to 3; or Y is SO₂; R₁ is phenyl that isunsubsituted or substituted by up to three substituents selected fromamino, mono- or disubstituted amino wherein the substituents areselected independently from lower alkyl, hydroxy-lower alkyl,phenyl-lower alkyl, lower alkanoyl, benzoyl and substituted benzoylwherein the phenyl radical is substituted by one or two substituentsselected from nitro, amino, halogen, N-lower alkylamino, N,N-di-loweralkylamino, hydroxy, cyano, carboxy, lower-alkoxycarbonyl, loweralkanoyl and carbamoyl, and phenyl-lower alkoxycarbonyl wherein thephenyl radical radical is substituted by one or two substituentsselected from nitro, amino, halogen, N-lower alkylamino, N,N-di-loweralkylamino, hydroxy, cyano, carboxy, lower-alkoxycarbonyl, loweralkanoyl and carbamoyl; lower alkyl; substituted lower alkyl where up tothree substituents are present independently selected from the groupcontaining halogen, N-lower alkylamino, N,N-di-lower alkylamino, N-loweralkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl andphenyl-lower alkoxycarbonyl; hydroxy, lower alkoxy; phenyl-lower alkoxy;phenyloxy; halogen-lower alkoxy, lower alkanoyloxy; benzoyloxy; loweralkoxycarbonyloxy; phenyl-lower alkoxycarbonyloxy; nitro; cyano;carboxy; lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl;phenyloxycarbonyl; lower alkylcarbonyl; carbamoyl; N-mono- orN,N-disubstituted carbamoyl that is substituted by one or twosubstituents independently selected from lower alkyl, phenyl-lower alkyland hydroxy-lower alkyl, at the terminal nitrogen atom; amidino;guanidino; mercapto; sulfo; lower alkylthio; phenylthio; phenyl-loweralkylthio; lower alkylphenylthio; lower alkylsulfinyl; phenylsulfinyl;phenyl-lower alkylsulfinyl; lower alkylphenylsulfinyl; loweralkanesulfonyl; phenylsulfonyl; phenyl-lower alkylsulfonyl; loweralkylphenylsulfonyl; lower alkenyl; lower alkanoyl; halogen-loweralkylmercapto; halogen-lower alkylsulfonyl; dihydroxybora (-B(OH)₂); andlower alkylene dioxy bound at adjacent C-atoms of the ring; R₂ isimidazolyl, quinolyl, naphthyridinyl, or a moiety of the formula Ib orIc

wherein r is 0 to 2; A, B, D, and E are, independently of one another, Nor CH, with the stipulation that not more than 2 of these radicals areN; preferably; and Q is lower alkyl, hydroxy, lower alkoxy, lowerthioalkyl or halogen; any of R₃, R₄, R₅ and R₆, independently of theother, is H, fluorine or lower alkyl; and R₇ and R₈, independently ofeach other, are H or lower alkyl; or a N-oxide or a pharmaceuticallyacceptable salt thereof.
 8. A compound of formula I according to claim5, wherein W is O; X is NR₈; Y is CHR₉-(CH₂)_(n) wherein R₉ is H ormethyl, and n is 0; or Y is SO₂; R₁ is phenyl, naphthyl or5,6,7,8-tetrahydronaphthyl which is in each case either unsubstituted orindependently substituted by one or two substituents selected from thegroup comprising halogen; lower alkyl; lower alkoxy; hydroxy; phenyl;phenoxy; halogen-lower alkoxy; halogen-lower alkyl; loweralkoxycarbonyl; N-lower alkyl carbamoyl; lower alkylsulfinyl; loweralkanesulfonyl; and lower alkoxycarbonyl lower alkyl; R₂ is imidazolyl,quinolyl, naphthyridinyl, 2-methyl-pyridin-4-yl, 3-pyridyl or 4-pyridyl;any of R₃, R₄, R₅ and R₆, independently of the other, are H, methyl orchloro; or R₃ and R₄ together represent methylene dioxy and R₅ and R₆,independently of the other, are H, methyl or chloro; and R₇ and R₈,independently of each other, are H, fluorine or methyl; or a N-oxide ora pharmaceutically acceptable salt thereof.
 9. A compound of formula Iaccording to claim 5, wherein W is O; X is NR₈; Y is CHR₉-(CH₂)_(n)wherein R₉ is H or methyl, and n is 0; or Y is SO₂; R₁ is phenyl whichis either unsubstituted or independently substituted by one or twosubstituents selected from the group comprising halogen; lower alkyl;halogen-lower alkyl; lower alkylsulfinyl; and lower alkanesulfonyl; R₂is imidazolyl, quinolyl, naphthyridinyl, 2-methyl-pyridin-4-yl,3-pyridyl or 4-pyridyl; any of R₃, R₄, R₅ and Re₆, independently of theother, is H or methyl; and R₇ and R₈, independently of each other, are Hor methyl; or a N-oxide or a pharmaceutically acceptable salt thereof.10. A compound of formula I according to claim 5, wherein W is O; X isNR₈; Y is CHR₉-(CH₂)_(n) wherein R₉ is H or methyl, and n is 0; or Y isSO₂; R₁ is phenyl which is either unsubstituted or independentlysubstituted by one or two substituents selected from the groupcomprising halogen; lower alkyl; halogen-lower alkyl; loweralkylsulfinyl; and lower alkanesulfonyl; R₂ is imidazolyl, quinolyl,2-methyl-pyridin-4-yl or 4-pyridyl; any of R₃, R₄, R₅ and R₆,independently of the other, is H or methyl; and R₇ and R₈, independentlyof each other, are H or methyl; or a salt thereof.
 11. A compound offormula I according to claim 5, wherein W is O; X is NR₈; Y is CH₂; R₁is phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl which is in each caseeither unsubstituted or independently substituted by one or twosubstituents selected from the group comprising halogen; lower alkyl;lower alkoxy; hydroxy; phenyl; phenoxy; halogen-lower alkoxy; loweralkoxycarbonyl; N-lower alkyl carbamoyl; and lower alkoxycarbonyl loweralkyl; R₂ is 4-pyridyl; any of R₃, R₄, R₅ and R₆, independently of theother, are H, methyl or chloro; or R₃ and R₄ together representmethylene dioxy and R₅ and R₆, independently of the other, are H, methylor chloro; and R₇ and R₈ are H; or a N-oxide or a pharmaceuticallyacceptable salt thereof.
 12. A compound of formula I according to claim5 selected from2-[(4-pyridyl)methyl]amino-N-(4-trifluoromethylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(4-methylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(3-fluoro-4-methylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(4-chloro-3-trifluoromethylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(3-chloro-5-trifluoromethylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(4-methylphenyl)-6-methylbenzamide; and2-[(4-quinolyl)methyl]amino-N-(4-chloromethylphenyl)benzamide; or apharmaceutically acceptable salt thereof.
 13. A compound of formula Iaccording to claim 5 selected from2-[(4-pyridyl)methyl]amino-N-[3-fluoro-(4-trifluoromethyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-phenylbenzamide;2-[(4-pyridyl)methyl]amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[3-fluoro-5-(trifluoromethyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[3,5-(bistrifluoromethyl)phenyl]benzamide;2-1(4-pyridyl)methyl]amino-N-[3,4-bis-(trifluoromethyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[3-(1 ,1 -dimethylethyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-(3cyanophenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(3-methylthio)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-(3-acetylaminophenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-[3-[(aminocarbonyl)amino]phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[3-(dimethylamino)phenyl]benzamide;5-methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;3-methyl-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;4,5-difluoro-2-[(4-pyridyl)methylamino-N-[3(trifluoromethyl)phenylbenzamide;2-[(4pyridyl)methyl]amino-N′-methyl-N′-[3-(trifluoromethyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-[(3-methylsulphonyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[(3-methylsulphinylphenyl]benzamide;2-1(4-pyridyl)methyl]amino-N-[4-(1 , -dimethylethyl)phenylbenzamide;2-[(4-pyridyl)methyl]amino-N-(3-chlorophenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(3-bromophenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(3-methylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(3-benzoylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-[3-(aminocarbonyl)phenyl]benzamide;2-[(3-pyridyl)methyl]amino-[N-3-(trifluoromethyl)phenylbenzamide;2-[(4-quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;2-[(5-quinolinyl)methyl]amino-[3-(trifluoromethyl)phenyl]benzamide;2-[(4-(2-methyl)pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenylbenzamide;2-[(4-(1,2-dihydro-2-oxo)pyridyl)methyl]amino-N-3-(trifluoromethyl)phenyl)-benzamide;2-[(4quinolinyl)methyl]amino-N-(4-chlorophenyl)benzamide;2-[(2-imidazolyl)methyl]amino-4(4chlorophenyl)benzamide;2-[2-(4-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenylbenzamide;2-[2-(3-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenylbenzamide;2-[1-methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;2-[(1oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;and2-[(4-pyridyl)methyl]methylamino-N-[3-(trifluoromethyl)phenyl]benzamide;or a pharmaceutically acceptable salt thereof.
 14. A compound of formulaI according to claim 5 selected from2-[(4-pyridyl)methyl]amino-N-(4-chloronaphthyl)benzamide;6-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;6-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;3,4-methylendioxy-6-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;4,5-dimethyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-/(7-hydroxynaphthyl)benzamide;2-1(4-pyridyl)methyl]amino-N-(8-hydroxy-2-naphthyl)benzamide;4-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;5-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(5,6,7,8-tetrahydronaphthyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(4-biphenyl)benzamide;5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(naphthyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(2-napthyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(4-methoxyphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-[4-(trifluoromethoxy)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-1(4-methoxy-2-naphthyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(3-bromo-2-naphthyl)benzamide;2-[(4-pyridyl)methyl]amino-N-[4-(isopropoxycarbonyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[4-(trifluoromethoxy)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-[4-(isopropylcarbamoyl)phenyl]benzamide;2-[(4-pyridyl)methyl]amino-N-(3-chloro-4-methylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-(2-methylphenyl)benzamide;2-[(4-pyridyl)methyl]amino-N-[3-(methoxycarbonylmethyl)phenyl]benzamide;and 2-[(4-pyridyl)methyl]amino-N-(4-phenoxyphenyl)benzamide; or apharmaceutically acceptable salt thereof.
 15. A compound of formula Iaccording to any one of claims 5 to 14, or a N-oxide thereof or apharmaceutically acceptable salt of such a compound, for use in a methodfor the treatment of the human or animal body.
 16. A pharmaceuticalpreparation, comprising a compound of formula I according to any one ofclaims 5 to 14, or a N-oxide or a pharmaceutically acceptable saltthereof, or a hydrate or solvate thereof, and at least onepharmaceutically acceptable carrier.
 17. A process for the preparationof a compound of formula I according to claim 5, or a N-oxide or apharmaceutically acceptable salt thereof, characterized in that a) forthe synthesis of a compound of the formula I wherein X represents NR₈,where R₈ is hydrogen and Y represents CHR₉-(CH₂)_(n), each as indicatedfor a compound of formula I, and the remaining symbols W, R₁, R₂, R₃,R₄, R₅, R₆ and R₇ are as defined for a compound of the formula I, ananiline derivative of the formula II

wherein W, R₁, R₃, R₄, R₅, R₆ and R₇ are as defined for a compound ofthe formula I, is reacted with a carbonyl compound of the formula IIIR₂-(CH₂)_(n)-C(R₉)═O   (III) wherein n, R₂ and R₉ are as defined for acompound of the formula I in the presence of a reducing agent; or b) forthe synthesis of a compound of the formula I wherein X is SO₂ and theremaining symbols R₁, R₂, R₃, R₄, R₅, R₆, R₇, W and X are as defined fora compound of the formula I, an aniline derivative of the formula II asdefined under process variante a) is reacted with an acid of the formulaIVa R₂-Y—OH   (IVa) or a reactive derivative thereof; or with a compoundof formula IVb, R₂-Y-Hal′  (IVb) wherein Hal′ is chloro, bromo or iodo;or c) for the synthesis of compounds of the formula I wherein Xrepresents NR₈, Y represents CR₉R₁₀-(CH₂)_(n) and the remaining symbolsR₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined for a compound of theformula I, a halogen derivative of the formula V

wherein Hal represents iodine, bromine or chlorine and W, R₁, R₃, R₄,R₅, R₆ and R₇ are as defined for a compound of the formula I, is reactedwith am amine of the formula VI R₂-(CH₂)_(n)-C(R₉)(R₁₀)-NHR₈   (VI)wherein n, R₂, R₈, R₉ and R₁₀ are as defined for a compound of theformula I in the presence of an appropriate catalyst in an inert solventin the presence of an aprotic base; where the starting compounds definedin a), b) or c) may also be present with functional groups in protectedform if necessary and/or in the form of salts, provided a salt-forminggroup is present and the reaction in salt form is possible; anyprotecting groups in a protected derivative of a compound of the formulaI are removed; and, if so desired, an obtainable compound of formula Iis converted into another compound of formula I or a N-oxide thereof, afree compound of formula I is converted into a salt, an obtainable saltof a compound of formula I is converted into the free compound oranother salt, and/or a mixture of isomeric compounds of formula I isseparated into the individual isomers.